New pyrazolopyrimidine derivatives as nik inhibitors

ABSTRACT

The present invention relates to pharmaceutical agents useful for therapy and/or prophylaxis in a mammal, and in particular to inhibitors of NF-κB-inducing kinase (NIK—also known as MAP3K14) useful for treating diseases such as cancer, inflammatory disorders, metabolic disorders and autoimmune disorders. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes to prepare such compounds and compositions, and to the use of such compounds or pharmaceutical compositions for the prevention or treatment of diseases such as cancer, inflammatory disorders, metabolic disorders including obesity and diabetes, and autoimmune disorders.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical agents useful fortherapy and/or prophylaxis in a mammal, and in particular to inhibitorsof NF-κB-inducing kinase (NIK—also known as MAP3K14) useful for treatingdiseases such as cancer, inflammatory disorders, metabolic disordersincluding obesity and diabetes, and autoimmune disorders. The inventionis also directed to pharmaceutical compositions comprising suchcompounds, to processes to prepare such compounds and compositions, andto the use of such compounds or pharmaceutical compositions for theprevention or treatment of diseases such as cancer, inflammatorydisorders, metabolic disorders including obesity and diabetes, andautoimmune disorders.

BACKGROUND OF THE INVENTION

The present invention relates to pharmaceutical agents useful fortherapy and/or prophylaxis in a mammal, and in particular to inhibitorsof NF-κB-inducing kinase (NIK—also known as MAP3K14) useful for treatingdiseases such as cancer and inflammatory disorders. Nuclear factor-kappaB (NF-κB) is a transcription factor regulating the expression of variousgenes involved in the immune response, cell proliferation, apoptosis,and carcinogenesis. NF-κB dependent transcriptional activation is atightly controlled signaling pathway, through sequential eventsincluding phosphorylation and protein degradation. NIK is aserine/threonine kinase which regulates NF-κB pathway activation. Thereare two NF-κB signaling pathways, the canonical and the non-canonical.NIK has a role in both but has been shown to be indispensable for thenon-canonical signaling pathway where it phosphorylates IKKα, leading tothe partial proteolysis of p100; liberating p52 which thenheterodimerizes with RelB, translocates to the nucleus and mediates geneexpression. The non-canonical pathway is activated by only a handful ofligands such as CD40 ligands, B-cell activating factor (BAFF),lymphotoxin β receptor ligands and TNF-related weak inducer of apoptosis(TWEAK) and NIK has been shown to be required for activation of thepathway by these ligands. Because of its key role, NIK expression istightly regulated. Under normal non-stimulated conditions NIK proteinlevels are very low, this is due to its interaction with a range of TNFreceptor associated factors (TRAF), which are ubiquitin ligases andresult in degradation of NIK. It is believed that when the non-canonicalpathway is stimulated by ligands, the activated receptors now competefor TRAFs, dissociating the TRAF-NIK complexes and thereby increasingthe levels of NIK. (Thu and Richmond, Cytokine Growth F. R. 2010, 21,213-226)

Research has shown that blocking the NF-κB signaling pathway in cancercells can cause cells to stop proliferating, to die and to become moresensitive to the action of other anti-cancer therapies. A role for NIKhas been shown in the pathogenesis of both hematological malignanciesand solid tumours.

The NF-κB pathway is dysregulated in multiple myeloma due to a range ofdiverse genetic abnormalities that lead to the engagement of thecanonical and non-canonical pathways (Annuziata et al. Cancer Cell 2007,12, 115-130; Keats et al. ibid 2007, 12, 131-144; Demchenko et al. Blood2010, 115, 3541-3552). Myeloma patient samples frequently have increasedlevels of NIK activity. This can be due to chromosomal amplification,translocations (that result in NIK proteins that have lost TRAF bindingdomains), mutations (in the TRAF binding domain of NIK) or TRAF loss offunction mutations. Researchers have shown that myeloma cell lines canbe dependent on NIK for proliferation; in these cell lines if NIKactivity is reduced by either shRNA or compound inhibition, this leadsto a failure in NF-κB signaling and the induction of cell death(Annuziata 2007).

In a similar manner, mutations in TRAF and increased levels of NIK havealso been seen in samples from Hodgkin lymphoma (HL) patients. Onceagain proliferation of cell lines derived from HL patients issusceptible to inhibition of NIK function by both shRNA and compounds(Ranuncolo et al. Blood First Edition Paper, 2012, DOI10.1182/blood-2012-01-405951).

NIK levels are also enhanced in adult T cell leukemia (ATL) cells andtargeting NIK with shRNA reduced ATL growth in vivo (Saitoh et al. Blood2008, 111, 5118-5129). It has been demonstrated that the API2-MALT1fusion oncoprotein created by the recurrent translocationt(11;18)(q21;q21) in mucosa-associated lymphoid tissue (MALT) lymphomainduces proteolytic cleavage of NF-κB-inducing kinase (NIK) at arginine325. NIK cleavage generates a C-terminal NIK fragment that retainskinase activity and is resistant to proteasomal degradation (due to lossof TRAF binding region). The presence of this truncated NIK leads toconstitutive non-canonical NF-κB signaling, enhanced B cell adhesion,and apoptosis resistance. Thus NIK inhibitors could represent a newtreatment approach for refractory t(11;18)-positive MALT lymphoma(Rosebeck et al. Science 2011, 331, 468-472).

NIK aberrantly accumulates in diffuse large B-cell lymphoma (DLBCL)cells due to constitutive activation of B-cell activation factor (BAFF)through interaction with autochthonous B-lymphocyte stimulator (BLyS)ligand. NIK accumulation in human DLBCL cell lines and patient tumorsamples suggested that constitutive NIK kinase activation is likely tobe a key signaling mechanism involved in abnormal lymphoma tumor cellproliferation. Growth assays showed that using shRNA to inhibit NIKkinase protein expression in GCB- and ABC-like DLBCL cells decreasedlymphoma cell growth in vitro, implicating NIK-induced NF-κB pathwayactivation as having a significant role in DLBCL proliferation (Pham etal. Blood 2011, 117, 200-210).

As mentioned a role of NIK in tumour cell proliferation is notrestricted to hematological cells, there are reports that NIK proteinlevels are stabilised in some pancreatic cancer cell lines and as seenin blood cells proliferation of these pancreatic cancer lines aresusceptible to NIK siRNA treatment (Nishina et al. Biochem. Bioph. Res.Co. 2009, 388, 96-101). Constitutive activation of NF-κB, ispreferentially involved in the proliferation of basal-like subtypebreast cancer cell lines, including elevated NIK protein levels inspecific lines (Yamamoto et al. Cancer Sci. 2010. 101, 2391-2397). Inmelanoma tumours, tissue microarray analysis of NIK expression revealedthat there was a statistically significant elevation in NIK expressionwhen compared with benign tissue. Moreover, shRNA techniques were usedto knock-down NIK, the resultant NIK-depleted melanoma cell linesexhibited decreased proliferation, increased apoptosis, delayed cellcycle progression and reduced tumor growth in a mouse xenograft model(Thu et al. Oncogene 2011, 1-13). A wealth of evidence showed that NF-κBis often constitutively activated in non-small cell lung cancer tissuespecimens and cell lines. Depletion of NIK by RNAi induced apoptosis andaffected efficiency of anchorage-independent NSCLC cell growth.

In addition research has shown that NF-κB controls the expression ofmany genes involved in inflammation and that NF-κB signalling is foundto be chronically active in many inflammatory diseases, such asrheumatoid arthritis, inflammatory bowel disease, sepsis and others.Thus pharmaceutical agents capable of inhibiting NIK and therebyreducing NF-κB signaling pathway can have a therapeutic benefit for thetreatment of diseases and disorders for which over-activation of NF-κBsignaling is observed.

Dysregulated NF-κB activity is associated with colonic inflammation andcancer, and it has been shown that Nlrp12 deficient mice were highlysusceptible to colitis and colitis-associated colon cancer. In thiscontext work showed that NLRP12 functions as a negative regulator of theNF-κB pathway through its interaction and regulation of NIK and TRAF3,and as a checkpoint of critical pathways associated with inflammationand inflammation-associated tumorigenesis (Allen et al. Immunity 2012,36, 742-754).

Tumor necrosis factor (TNF)-α, is secreted in response to inflammatorystimuli in diseases such as rheumatoid arthritis and inflammatory boweldisease. In a series of experiments in colonic epithelial cells andmouse embryonic fibroblasts, TNF-α mediates both apoptosis andinflammation, stimulating an inflammatory cascade through thenon-canonical pathway of NF-κB activation, leading to increased nuclearRelB and p52. TNF-α induced the ubiquitination of TRAFs, which interactswith NIK, leading to increased levels of phospho-NIK (Bhattacharyya etal. J Biol. Chem. 2011, 285, 39511-39522).

Inflammatory responses are a key component of chronic obstructivepulmonary disease (COPD) as such it has been shown that NIK plays a keyrole in exacerbating the disease following infection with theGram-negative bacterium nontypeable Hemophilus influenza (Shuto et al.PNAS 2001, 98, 8774-8779). Likewise cigarette smoke (CS) containsnumerous reactive oxygen/nitrogen species, reactive aldehydes, andquinones, which are considered to be some of the most important causesof the pathogenesis of chronic inflammatory lung diseases, such as COPDand lung cancer. Increased levels of NIK and p-IKKα have been observedin peripheral lungs of smokers and patients with COPD. In addition ithas been shown that endogenous NIK is recruited to promoter sites ofpro-inflammatory genes to induce post-translational modification ofhistones, thereby modifying gene expression profiles, in response to CSor TNFα (Chung et al. PLoS ONE 2011, 6(8): e23488.doi:10.1371/journal.pone.0023488). A shRNA screen was used in an invitro model of oxidative stress induced cell death (as a model of COPD)to interrogate a human druggable genome siRNA library in order toidentify genes that modulate the cellular response to stress. NIK wasone of the genes identified in this screen as a potential newtherapeutic target to modulate epithelial apoptosis in chronic lungdiseases (Wixted et al. Toxicol. In Vitro 2010, 24, 310-318).

Diabetic individuals can be troubled by a range of additionalmanifestations associated with inflammation. One such complication iscardiovascular disease and it has been shown that there are elevatedlevels of p-NIK, p-IKK-α/β and p-IκB-α in diabetic aortic tissues (Bitaret al. Life Sci. 2010, 86, 844-853). In a similar manner, NIK has beenshown to regulate proinflammatory responses of renal proximal tubularepithelial cells via mechanisms involving TRAF3. This suggests a rolefor NF-κB noncanonical pathway activation in modulating diabetes-inducedinflammation in renal tubular epithelium (Zhao et al. Exp. Diabetes Res.2011, 1-9). The same group has shown that NIK plays a critical role innoncanonical NF-κB pathway activation, induced skeletal muscle insulinresistance in vitro, suggesting that NIK could be an importanttherapeutic target for the treatment of insulin resistance associatedwith inflammation in obesity and type 2 diabetes (Choudhary et al.Endocrinology 2011, 152, 3622-3627).

NF-κB is an important component of both autoimmunity and bonedestruction in rheumatoid arthritis (RA). Mice lacking functional NIKhave no peripheral lymph nodes, defective B and T cells, and impairedreceptor activator of NF-κB ligand—stimulated osteoclastogenesis. Aya etal. (J. Clin. Invest. 2005, 115, 1848-1854) investigated the role of NIKin murine models of inflammatory arthritis using Nik−/− mice. The serumtransfer arthritis model was initiated by preformed antibodies andrequired only intact neutrophil and complement systems in recipients.While Nik−/− mice had inflammation equivalent to that of Nik+/+controls, they showed significantly less periarticularosteoclastogenesis and less bone erosion. In contrast, Nik−/− mice werecompletely resistant to antigen-induced arthritis (AIA), which requiresintact antigen presentation and lymphocyte function but not lymph nodes.Additionally, transfer of Nik+/+ splenocytes or T cells to Rag2−/− miceconferred susceptibility to AIA, while transfer of Nik−/− cells did not.Nik−/− mice were also resistant to a genetic, spontaneous form ofarthritis, generated in mice expressing both the KRN T cell receptor andH-2g7. The same group used transgenic mice with OC-lineage expression ofNIK lacking its TRAF3 binding domain (NT3), to demonstrate thatconstitutive activation of NIK drives enhanced osteoclastogenesis andbone resorption, both in basal conditions and in response toinflammatory stimuli (Yang et al. PLoS One 2010, 5, 1-9, e15383). Thusthis group concluded that NIK is important in the immune andbone-destructive components of inflammatory arthritis and represents apossible therapeutic target for these diseases.

It has also been hypothesized that manipulating levels of NIK in T cellsmay have therapeutic value. Decreasing NIK activity in T cells mightsignificantly ameliorate autoimmune and alloresponses, like GVHD (GraftVersus Host Disease) and transplant rejection, without crippling theimmune system as severely as do inhibitors of canonical NF-κBactivation.

WO2010/042337 describes novel 6-azaindole aminopyrimidine derivativeshaving NIK inhibitory activity.

WO2009/158011 describes alkynyl alcohols as kinase inhibitors.

WO2012/123522 describes 6,5-heterocyclic propargylic alcohol compoundsand uses therefor.

DESCRIPTION OF THE INVENTION

The present invention concerns novel compounds of Formula (I):

and tautomers and stereoisomeric forms thereof, wherein

R¹ is selected from the group of hydrogen; C₁₋₄alkyl; and C₁₋₄alkylsubstituted with one or more fluoro substituents;

R² is selected from the group of hydrogen; C₁₋₄alkyl; C₁₋₄alkylsubstituted with one or more fluoro substituents; C₃₋₆cycloalkyl; andHet¹;

or R¹ and R² together with the carbon atom to which they are attachedform a C₃₋₆cycloalkyl;

Het¹ is a heteroaryl selected from the group of thienyl, thiazolyl,pyrrolyl, oxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, isoxazolyl,isothiazolyl, pyridinyl and pyrimidinyl, each of which may be optionallysubstituted with one or two substituents independently selected fromhalogen, cyano, C₁₋₄alkyl, C₁₋₄alkyloxy, C₁₋₄alkyl substituted with oneor more fluoro substituents, and C₁₋₄alkyloxy substituted with one ormore fluoro substituents;

X is N or CR⁹;

R⁹ is selected from hydrogen and halogen;

R³ is selected from the group of hydrogen; halogen; cyano;C₃₋₆cycloalkyl; C₁₋₆alkyl;

Het⁴; C₁₋₆alkyl substituted with one or more fluoro substituents;—OC₁₋₆alkyl;

—OC₁₋₆alkyl substituted with one or more fluoro substituents; andC₁₋₆alkyl substituted with one substituent selected from —NR^(3a)R^(3b)and —OC₁₋₄alkyl;

Het⁴ is a heteroaryl selected from the group of piperidinyl,tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl,piperazinyl, morpholinyl and oxetanyl, each of which may be optionallysubstituted with one or two substituents independently selected fromfluoro, C₁₋₄alkyl, —OC₁₋₄alkyl, C₃₋₆cycloalkyl and C₁₋₄alkyl substitutedwith one or more fluoro substituents;

R^(3a) and R^(3b) are each independently selected from hydrogen andC₁₋₄alkyl;

R⁴ is hydrogen;

R⁵ is selected from the group of hydrogen; cyano; C₁₋₄alkyl; C₁₋₄alkylsubstituted with one or more fluoro substituents; C₁₋₄alkyl substitutedwith one substituent selected from the group of —NR^(5a)R^(5b),—OC₁₋₄alkyl, and Het⁵;

R^(5a) and R^(5b) are each independently selected from the group ofhydrogen and C₁₋₄alkyl;

Het⁵ is a heterocyclyl selected from the group of piperidinyl,piperazinyl, morpholinyl, tetrahydropyranyl, pyrrolidinyl,tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may beoptionally substituted with one or two substituents independentlyselected from fluoro, C₁₋₄alkyl, —OC₁₋₄alkyl, C₃₋₆cycloalkyl andC₁₋₄alkyl substituted with one or more fluoro substituents;

R⁶ is selected from the group of hydrogen; Het²; R⁸; C₁₋₆alkyloptionally substituted with one Het³; and C₂₋₆alkyl substituted with oneor more substituents independently selected from the group of fluoro,—NR^(6a)R^(6b), and —OR^(6c)c,

R^(6a), R^(6b) and R^(6c) are each independently selected from hydrogenand C₁₋₆alkyl;

Het² is a heterocyclyl, bound through any available carbon atom,selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl,tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may beoptionally substituted with one or two substituents independentlyselected from fluoro, C₁₋₄alkyl, —OC₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkylsubstituted with one —OC₁₋₄alkyl, C₁₋₄alkyl substituted with oneC₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one or more fluorosubstituents;

Het³ is a heterocyclyl selected from the group of morpholinyl,piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl,tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may beoptionally substituted with one or two substituents independentlyselected from fluoro, C₁₋₄alkyl, —OC₁₋₄alkyl, C₃₋₆cycloalkyl,

C₁₋₄alkyl substituted with one —OC₁₋₄alkyl,

C₁₋₄alkyl substituted with one C₃₋₆cycloalkyl,

and C₁₋₄alkyl substituted with one or more fluoro substituents;

R⁸ is C₃₋₆cycloalkyl optionally substituted with one or two substituentsindependently selected from fluoro, C₁₋₄alkyl, —OC₁₋₄alkyl, C₁₋₄alkylsubstituted with one —OC₁₋₄alkyl, and C₁₋₄alkyl substituted with one ormore fluoro substituents;

R⁷ is selected from the group of hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl andC₁₋₄alkyl substituted with one —OC₁₋₄alkyl;

and the pharmaceutically acceptable salts, and the solvates thereof.

DETAILED DESCRIPTION OF THE INVENTION

The term ‘halo’ or ‘halogen’ as used herein represents fluoro, chloro,bromo and iodo.

The prefix ‘C_(x-y)’ (where x and y are integers) as used herein refersto the number of carbon atoms in a given group. Thus, a C₁₋₆alkyl groupcontains from 1 to 6 carbon atoms, a C₃₋₆cycloalkyl group contains from3 to 6 carbon atoms, and so on.

The term ‘C₁₋₄alkyl’ as used herein as a group or part of a grouprepresents a straight or branched chain saturated hydrocarbon radicalhaving from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl,isopropyl, n-butyl, s-butyl, t-butyl and the like.

The term ‘C₁₋₆alkyl’ as used herein as a group or part of a grouprepresents a straight or branched chain saturated hydrocarbon radicalhaving from 1 to 6 carbon atoms such as the groups defined for C₁₋₄alkyland n-pentyl, n-hexyl, 2-methylbutyl and the like.

The term ‘C₂₋₆alkyl’ as used herein as a group or part of a grouprepresents a straight or branched chain saturated hydrocarbon radicalhaving from 2 to 6 carbon atoms such as ethyl, n-propyl, isopropyl,n-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, 2-methylbutyl and thelike.

The term ‘C₃₋₆cycloalkyl’ as used herein as a group or part of a grouprepresents cyclic saturated hydrocarbon radicals having from 3 to 6carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term ‘C₁₋₄alkyloxy’ as a group or part of a group refers to aradical having the Formula —OR^(c) wherein R^(c) is C₁₋₄alkyl.Non-limiting examples of suitable C₁₋₄alkyloxy include methyloxy (alsomethoxy), ethyloxy (also ethoxy), propyloxy, isopropyloxy, butyloxy,isobutyloxy, sec-butyloxy and tert-butyloxy.

The term ‘C₁₋₆alkyl substituted with one or more substituents’ as usedherein as a group or part of a group refers to a C₁₋₆alkyl group asdefined herein wherein one or more than one hydrogen atom is replacedwith another group. The term therefore includes monosubstitutedC₁₋₆alkyl and also polysubstituted C₁₋₆alkyl. There may be one, two,three or more hydrogen atoms replaced with a substituent, so the fullyor partially substituted C₁₋₆alkyl may have one, two, three or moresubstituents. Examples of such groups wherein the substituent is forexample, fluoro include fluoromethyl, difluoromethyl, trifluoromethyl,fluoroethyl, trifluoroethyl and the like.

In general, whenever the term “substituted” is used in the presentinvention, it is meant, unless otherwise is indicated or is clear fromthe context, to indicate that one or more hydrogens, in particular from1 to 4 hydrogens, more in particular from 1 to 3 hydrogens, preferably 1or 2 hydrogens, more preferably 1 hydrogen, on the atom or radicalindicated in the expression using “substituted” are replaced with aselection from the indicated group, provided that the normal valency isnot exceeded, and that the substitution results in a chemically stablecompound, i.e. a compound that is sufficiently robust to surviveisolation to a useful degree of purity from a reaction mixture, andformulation into a therapeutic agent.

Combinations of substituents and/or variables are permissible only ifsuch combinations result in chemically stable compounds. “Stablecompound” is meant to indicate a compound that is sufficiently robust tosurvive isolation to a useful degree of purity from a reaction mixture,and formulation into a therapeutic agent.

C(O) or C(═O) represents a carbonyl moiety.

S(O)₂ or SO₂ represents a sulfonyl moiety.

Substituents covered by the term “Het^(x)” (where x is an integer; orHet^(x) refers to Het^(1a), Het^(1b), Het^(2a), . . . ), “heterocyclyl”or “heteroaryl” may be attached to the remainder of the molecule ofFormula (I) through any available ring carbon or heteroatom asappropriate, if not otherwise specified.

Whenever substituents are represented by chemical structure, “—”represents the bond of attachment to the remainder of the molecule ofFormula (I).

When any variable occurs more than one time in any constituent, eachdefinition is independent.

When any variable occurs more than one time in any formula (e.g. Formula(I)), each definition is independent.

The term “subject” as used herein, refers to an animal, preferably amammal (e.g. cat, dog, primate or human), more preferably a human, whois or has been the object of treatment, observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medicinal doctor orother clinician, which includes alleviation or reversal of the symptomsof the disease or disorder being treated.

The term “composition” is intended to encompass a product comprising thespecified ingredients in the specified amounts, as well as any productwhich results, directly or indirectly, from combinations of thespecified ingredients in the specified amounts.

The term “treatment”, as used herein, is intended to refer to allprocesses wherein there may be a slowing, interrupting, arresting orstopping of the progression of a disease, but does not necessarilyindicate a total elimination of all symptoms.

The term “compound(s) of the (present) invention” or “compound(s)according to the (present) invention” as used herein, is meant toinclude the compounds of Formula (I) and the pharmaceutically acceptablesalts, and the solvates thereof.

As used herein, any chemical formula with bonds shown only as solidlines and not as solid wedged or hashed wedged bonds, or otherwiseindicated as having a particular configuration (e.g. R, S) around one ormore atoms, contemplates each possible stereoisomer, or mixture of twoor more stereoisomers.

Hereinbefore and hereinafter, the term “compound(s) of Formula (I)” ismeant to include the tautomers thereof and the stereoisomeric formsthereof.

The terms “stereoisomers”, “stereoisomeric forms” or “stereochemicallyisomeric forms” hereinbefore or hereinafter are used interchangeably.

The invention includes all stereoisomers of the compounds of theinvention either as a pure stereoisomer or as a mixture of two or morestereoisomers.

Enantiomers are stereoisomers that are non-superimposable mirror imagesof each other. A 1:1 mixture of a pair of enantiomers is a racemate orracemic mixture.

Atropisomers (or atropoisomers) are stereoisomers which have aparticular spatial configuration, resulting from a restricted rotationabout a single bond, due to large steric hindrance. All atropisomericforms of the compounds of Formula (I) are intended to be included withinthe scope of the present invention.

Diastereomers (or diastereoisomers) are stereoisomers that are notenantiomers, i.e. they are not related as mirror images. If a compoundcontains a double bond, the substituents may be in the E or the Zconfiguration.

Substituents on bivalent cyclic (partially) saturated radicals may haveeither the cis- or trans-configuration; for example if a compoundcontains a disubstituted cycloalkyl group, the substituents may be inthe cis or trans configuration.

Therefore, the invention includes enantiomers, atropisomers,diastereomers, racemates, E isomers, Z isomers, cis isomers, transisomers and mixtures thereof, whenever chemically possible.

The meaning of all those terms, i.e. enantiomers, atropisomers,diastereomers, racemates, E isomers, Z isomers, cis isomers, transisomers and mixtures thereof are known to the skilled person.

The absolute configuration is specified according to theCahn-Ingold-Prelog system. The configuration at an asymmetric atom isspecified by either R or S. Resolved stereoisomers whose absoluteconfiguration is not known can be designated by (+) or (−) depending onthe direction in which they rotate plane polarized light. For instance,resolved enantiomers whose absolute configuration is not known can bedesignated by (+) or (−) depending on the direction in which they rotateplane polarized light.

When a specific stereoisomer is identified, this means that saidstereoisomer is substantially free, i.e. associated with less than 50%,preferably less than 20%, more preferably less than 10%, even morepreferably less than 5%, in particular less than 2% and most preferablyless than 1%, of the other stereoisomers. Thus, when a compound ofFormula (I) is for instance specified as (R), this means that thecompound is substantially free of the (S) isomer; when a compound ofFormula (I) is for instance specified as E, this means that the compoundis substantially free of the Z isomer; when a compound of Formula (I) isfor instance specified as cis, this means that the compound issubstantially free of the trans isomer.

Some of the compounds according to Formula (I) may also exist in theirtautomeric form. Such forms in so far as they may exist, although notexplicitly indicated in the above Formula (I) are intended to beincluded within the scope of the present invention. It follows that asingle compound may exist in both stereoisomeric and tautomeric form.

For use in medicine, the salts of the compounds of this invention referto non-toxic “pharmaceutically acceptable salts”. Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts which may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid.

Conversely, said salt forms can be converted into the free base form bytreatment with an appropriate base.

Furthermore, where the compounds of the invention carry an acidicmoiety, suitable pharmaceutically acceptable salts thereof may includealkali metal salts, e.g., sodium or potassium salts; alkaline earthmetal salts, e.g., calcium or magnesium salts; and salts formed withsuitable organic ligands, e.g., quaternary ammonium salts.

Representative acids which may be used in the preparation ofpharmaceutically acceptable salts include, but are not limited to, thefollowing: acetic acid, 2,2-dichloroactic acid, acylated amino acids,adipic acid, alginic acid, ascorbic acid, L-aspartic acid,benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid,(+)-camphoric acid, camphorsulfonic acid, capric acid, caproic acid,caprylic acid, cinnamic acid, citric acid, cyclamic acid,ethane-1,2-disulfonic acid, ethanesulfonic acid,2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaricacid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronicacid, L-glutamic acid, beta-oxo-glutaric acid, glycolic acid, hippuricacid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid,(±)-DL-lactic acid, lactobionic acid, maleic acid, (-)-L-malic acid,malonic acid, (±)-DL-mandelic acid, methanesulfonic acid,naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid,1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid,orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid,L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacicacid, stearic acid, succinic acid, sulfuric acid, tannic acid,(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid,trifluoromethylsulfonic acid, and undecylenic acid.

Representative bases which may be used in the preparation ofpharmaceutically acceptable salts include, but are not limited to, thefollowing: ammonia, L-arginine, benethamine, benzathine, calciumhydroxide, choline, dimethylethanolamine, diethanolamine, diethylamine,2-(diethylamino)-ethanol, ethanolamine, ethylene-diamine,N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodiumhydroxide, triethanolamine, tromethamine and zinc hydroxide.

Conversely, said salt forms can be converted into the free acid forms bytreatment with an appropriate acid.

The term solvate comprises the solvent addition forms as well as thesalts thereof, which the compounds of Formula (I) are able to form.Examples of such solvent addition forms are e.g. hydrates, alcoholatesand the like.

In the framework of this application, an element, in particular whenmentioned in relation to a compound according to Formula (I), comprisesall isotopes and isotopic mixtures of this element, either naturallyoccurring or synthetically produced, either with natural abundance or inan isotopically enriched form. Radiolabelled compounds of Formula (I)may comprise a radioactive isotope selected from the group of ²H (D),³H, ¹¹C, ¹⁸F, ¹²²I, ¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and ⁸²Br.Preferably, the radioactive isotope is selected from the group of ²H,³H, ¹¹C and ¹⁸F. More preferably, the radioactive isotope is ²H. Inparticular, deuterated compounds are intended to be included within thescope of the present invention.

The present invention relates in particular to compounds of Formula (I)as defined herein, and tautotners and stereoisomeric forms thereof,wherein

R¹ is selected from the group of hydrogen; C₁₋₄alkyl; and C₁₋₄alkylsubstituted with one or more fluoro substituents;

R² is selected from the group of C₁₋₄alkyl; C₁₋₄alkyl substituted withone or more fluoro substituents; C₃₋₆cycloalkyl; and Het¹;

or R¹ and R² together with the carbon atom to which they are attachedform a C₃₋₆cycloalkyl;

Het¹ is a heteroaryl selected from the group of thienyl, thiazolyl,pyrrolyl, oxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, isoxazolyl,isothiazolyl, pyridinyl and pyrimidinyl, each of which may be optionallysubstituted with one or two substituents independently selected fromhalogen, cyano, C₁₋₄alkyl, C₁₋₄alkyloxy, C₁₋₄alkyl substituted with oneor more fluoro substituents, and C₁₋₄alkyloxy substituted with one ormore fluoro substituents;

X is N or CR⁹;

R⁹ is selected from hydrogen and halogen;

R³ is selected from the group of hydrogen; halogen; cyano;C₃₋₆cycloalkyl; C₁₋₆alkyl;

C₁₋₆alkyl substituted with one or more fluoro substituents; —OC₁₋₆alkyl;—OC₁₋₆alkyl substituted with one or more fluoro substituents; andC₁₋₆alkyl substituted with one substituent selected from —NR^(3a)R^(3b)and —OC₁₋₄alkyl;

R^(3a) and R^(3b) are each independently selected from hydrogen andC₁₋₄alkyl;

R⁴ is hydrogen;

R⁵ is selected from the group of hydrogen; cyano; C₁₋₄alkyl; C₁₋₄alkylsubstituted with one or more fluoro substituents; C₁₋₄alkyl substitutedwith one substituent selected from the group of —NR^(5a)R^(5b), and—OC₁₋₄alkyl;

R^(5a) and R^(5b) are each independently selected from the group ofhydrogen and C₁₋₄alkyl;

R⁶ is selected from the group of hydrogen; Het²; R⁸; C₁₋₆alkyloptionally substituted with one Het³; and C₂₋₆alkyl substituted with oneor more substituents independently selected from the group of fluoro,—NR^(6a)R^(6b), and —OR^(6c),

R^(6a), R^(6b) and R^(6c) are each independently selected from hydrogenand C₁₋₆alkyl;

Het² is a heterocyclyl, bound through any available carbon atom,selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl,tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may beoptionally substituted with one or two substituents independentlyselected from fluoro, C₁₋₄alkyl, —OC₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkylsubstituted with one —OC₁₋₄alkyl, C₁₋₄alkyl substituted with oneC₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one or more fluorosubstituents;

Het³ is a heterocyclyl selected from the group of morpholinyl,piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl,tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may beoptionally substituted with one or two substituents independentlyselected from fluoro, C₁₋₄alkyl, —OC₁₋₄alkyl, C₃₋₆cycloalkyl,

C₁₋₄alkyl substituted with one —OC₁₋₄alkyl,

C₁₋₄alkyl substituted with one C₃₋₆cycloalkyl,

and C₁₋₄alkyl substituted with one or more fluoro substituents;

R⁸ is C₃₋₆cycloalkyl optionally substituted with one or two substituentsindependently selected from fluoro, C₁₋₄alkyl, —OC₁₋₄alkyl, C₁₋₄alkylsubstituted with one —OC₁₋₄alkyl, and C₁₋₄alkyl substituted with one ormore fluoro substituents;

R⁷ is selected from the group of hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl andC₁₋₄alkyl substituted with one —OC₁₋₄alkyl;

and the pharmaceutically acceptable salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I)as defined herein, and tautomers and stereoisomeric forms thereof,wherein

R¹ is selected from the group of hydrogen: C₁₋₄alkyl: and C₁₋₄alkylsubstituted with one or more fluoro substituents;

R² is selected from the group of C₁₋₄alkyl; C₁₋₄alkyl substituted withone or more fluoro substituents; C₃₋₆cycloalkyl; and Het¹;

Het¹ is a heteroaryl selected from the group of thienyl, thiazolyl,pyrrolyl, oxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, isoxazolyl,isothiazolyl, pyridinyl and pyrimidinyl, each of which may be optionallysubstituted with one or two substituents independently selected fromhalogen, cyano, C₁₋₄alkyl, C₁₋₄alkyloxy, C₁₋₄alkyl substituted with oneor more fluoro substituents, and C₁₋₄alkyloxy substituted with one ormore fluoro substituents;

X is N or CR⁹;

R⁹ is selected from hydrogen and halogen;

R³ is selected from the group of hydrogen; halogen; cyano;C₃₋₆cycloalkyl; C₁₋₆alkyl;

C₁₋₆alkyl substituted with one or more fluoro substituents; —OC₁₋₆alkyl;—OC₁₋₆alkyl substituted with one or more fluoro substituents; andC₁₋₆alkyl substituted with one substituent selected from —NR^(3a)R^(3b)and —OC₁₋₄alkyl;

R^(3a) and R^(3b) are each independently selected from hydrogen andC₁₋₄alkyl;

R⁴ is hydrogen;

R⁵ is selected from the group of hydrogen; cyano; C₁₋₄alkyl; C₁₋₄alkylsubstituted with one or more fluoro substituents; C₁₋₄alkyl substitutedwith one substituent selected from the group of —NR^(5a)R^(5b), and—OC₁₋₄alkyl;

R^(5a) and R^(5b) are each independently selected from the group ofhydrogen and C₁₋₄alkyl;

R⁶ is selected from the group of hydrogen; Het²; R⁸; C₁₋₆alkyloptionally substituted with one Het³; and C₂₋₆alkyl substituted with oneor more substituents independently selected from the group of fluoro,—NR^(6a)R^(6b), and —OR^(6c),

R^(6a), R^(6b) and R^(6c) are each independently selected from hydrogenand C₁₋₆alkyl;

Het² is a heterocyclyl, bound through any available carbon atom,selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl,tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may beoptionally substituted with one or two substituents independentlyselected from fluoro, C₁₋₄alkyl, —OC₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkylsubstituted with one —OC₁₋₄alkyl, C₁₋₄alkyl substituted with oneC₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one or more fluorosubstituents;

Het³ is a heterocyclyl selected from the group of morpholinyl,piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl,tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may beoptionally substituted with one or two substituents independentlyselected from fluoro, C₁₋₄alkyl, —OC₁₋₄alkyl, C₃₋₆cycloalkyl,

C₁₋₄alkyl substituted with one —OC₁₋₄alkyl,

C₁₋₄alkyl substituted with one C₃₋₆cycloalkyl,

and C₁₋₄alkyl substituted with one or more fluoro substituents;

R⁸ is C₃₋₆cycloalkyl optionally substituted with one or two substituentsindependently selected from fluoro, C₁₋₄alkyl, —OC₁₋₄alkyl, C₁₋₄alkylsubstituted with one —OC₁₋₄alkyl, and C₁₋₄alkyl substituted with one ormore fluoro substituents;

R⁷ is selected from the group of hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl andC₁₋₄alkyl substituted with one —OC₁₋₄alkyl;

and the pharmaceutically acceptable salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I)as defined herein, and tautomers and stereoisomeric forms thereof,wherein

R¹ is selected from the group of hydrogen; C₁₋₄alkyl; and C₁₋₄alkylsubstituted with one or more fluoro substituents;

R² is selected from the group of hydrogen; C₁₋₄alkyl; C₁₋₄alkylsubstituted with one or more fluoro substituents; C₃₋₆cycloalkyl; andHet¹;

or R¹ and R² together with the carbon atom to which they are attachedform a C₃₋₆cycloalkyl;

Het¹ is a heteroaryl selected from the group of thienyl, thiazolyl,pyrrolyl, oxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, isoxazolyl,isothiazolyl, pyridinyl and pyrimidinyl, each of which may be optionallysubstituted with one or two substituents independently selected fromhalogen, cyano, C₁₋₄alkyl, C₁₋₄alkyloxy, C₁₋₄alkyl substituted with oneor more fluoro substituents, and C₁₋₄alkyloxy substituted with one ormore fluoro substituents;

X is N;

R³ is selected from the group of hydrogen; halogen; cyano;C₃₋₆cycloalkyl; C₁₋₆alkyl;

Het⁴; C₁₋₆alkyl substituted with one or more fluoro substituents;—OC₁₋₆alkyl; —OC₁₋₆alkyl substituted with one or more fluorosubstituents; and C₁₋₆alkyl substituted with one substituent selectedfrom —NR^(3a)R^(3b) and —OC₁₋₄alkyl;

Het⁴ is a heteroaryl selected from the group of piperidinyl,tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl,piperazinyl, morpholinyl and oxetanyl, each of which may be optionallysubstituted with one or two substituents independently selected fromfluoro,

C₁₋₄alkyl, —OC₁₋₄alkyl, C₃₋₆cycloalkyl and C₁₋₄alkyl substituted withone or more fluoro substituents;

R^(3a) and R^(3b) are each independently selected from hydrogen andC₁₋₄alkyl;

R⁴ is hydrogen;

R⁵ is selected from the group of hydrogen; cyano; C₁₋₄alkyl; C₁₋₄alkylsubstituted with one or more fluoro substituents; C₁₋₄alkyl substitutedwith one substituent selected from the group of —NR^(5a)R^(5b),—OC₁₋₄alkyl, and Het⁵;

R^(5a) and R^(5b) are each independently selected from the group ofhydrogen and C₁₋₄alkyl;

Het⁵ is a heterocyclyl selected from the group of piperidinyl,piperazinyl, morpholinyl, tetrahydropyranyl, pyrrolidinyl,tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may beoptionally substituted with one or two substituents independentlyselected from fluoro, C₁₋₄alkyl, —OC₁₋₄alkyl, C₃₋₆cycloalkyl andC₁₋₄alkyl substituted with one or more fluoro substituents;

R⁶ is selected from the group of hydrogen; Het²; R⁸; C₁₋₆alkyloptionally substituted with one Het³; and C₂₋₆alkyl substituted with oneor more substituents independently selected from the group of fluoro,—NR^(6a)R^(6b), and —OR^(6c),

R^(6a), R^(6b) and R^(6c) are each independently selected from hydrogenand C₁₋₆alkyl;

Het² is a heterocyclyl, bound through any available carbon atom,selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl,tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may beoptionally substituted with one or two substituents independentlyselected from fluoro, C₁₋₄alkyl, —OC₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkylsubstituted with one —OC₁₋₄alkyl, C₁₋₄alkyl substituted with oneC₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one or more fluorosubstituents;

Het³ is a heterocyclyl selected from the group of morpholinyl,piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl,tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may beoptionally substituted with one or two substituents independentlyselected from fluoro, C₁₋₄alkyl, —OC₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkylsubstituted with one —OC₁₋₄alkyl,

C₁₋₄alkyl substituted with one C₃₋₆cycloalkyl,

and C₁₋₄alkyl substituted with one or more fluoro substituents;

R⁸ is C₃₋₆cycloalkyl optionally substituted with one or two substituentsindependently selected from fluoro, C₁₋₄alkyl, —OC₁₋₄alkyl, C₁₋₄alkylsubstituted with one —OC₁₋₄alkyl, and C₁₋₄alkyl substituted with one ormore fluoro substituents;

R⁷ is selected from the group of hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl and

C₁₋₄alkyl substituted with one —OC₁₋₄alkyl;

and the pharmaceutically acceptable salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I)as defined herein, and tautomers and stereoisomeric forms thereof,wherein

R¹ is selected from the group of hydrogen; C₁₋₄alkyl; and C₁₋₄alkylsubstituted with one or more fluoro substituents;

R² is selected from the group of hydrogen; C₁₋₄alkyl; C₁₋₄alkylsubstituted with one or more fluoro substituents; C₃₋₆cycloalkyl; andHet¹;

or R¹ and R² together with the carbon atom to which they are attachedform a C₃₋₆cycloalkyl;

Het¹ is a heteroaryl selected from the group of thienyl, thiazolyl,pyrrolyl, oxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, isoxazolyl,isothiazolyl, pyridinyl and pyrimidinyl, each of which may be optionallysubstituted with one or two substituents independently selected fromhalogen, cyano, C₁₋₄alkyl, C₁₋₄alkyloxy, C₁₋₄alkyl substituted with oneor more fluoro substituents, and C₁₋₄alkyloxy substituted with one ormore fluoro substituents;

X is CR⁹;

R⁹ is selected from hydrogen and halogen;

R³ is selected from the group of hydrogen; halogen; cyano;C₃₋₆cycloalkyl; C₁₋₆alkyl;

Het⁴; C₁₋₆alkyl substituted with one or more fluoro substituents;—OC₁₋₆alkyl; —OC₁₋₆alkyl substituted with one or more fluorosubstituents; and C₁₋₆alkyl substituted with one substituent selectedfrom —NR^(3a)R^(3b) and —OC₁₋₄alkyl;

Het⁴ is a heteroaryl selected from the group of piperidinyl,tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl,piperazinyl, morpholinyl and oxetanyl, each of which may be optionallysubstituted with one or two substituents independently selected fromfluoro,

C₁₋₄alkyl, —OC₁₋₄alkyl, C₃₋₆cycloalkyl and C₁₋₄alkyl substituted withone or more fluoro substituents;

R^(3a) and R^(3b) are each independently selected from hydrogen andC₁₋₄alkyl;

R⁴ is hydrogen;

R⁵ is selected from the group of hydrogen; cyano; C₁₋₄alkyl; C₁₋₄alkylsubstituted with one or more fluoro substituents; C₁₋₄alkyl substitutedwith one substituent selected from the group of —NR^(5a)R^(5b),—OC₁₋₄alkyl, and Het⁵;

R^(5a) and R^(5b) are each independently selected from the group ofhydrogen and C₁₋₄alkyl;

Het⁵ is a heterocyclyl selected from the group of piperidinyl,piperazinyl, morpholinyl, tetrahydropyranyl, pyrrolidinyl,tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may beoptionally substituted with one or two substituents independentlyselected from fluoro, C₁₋₄alkyl, —OC₁₋₄alkyl, C₃₋₆cycloalkyl andC₁₋₄alkyl substituted with one or more fluoro substituents;

R⁶ is selected from the group of hydrogen; Het²; R⁸; C₁₋₆alkyloptionally substituted with one Het³; and C₂₋₆alkyl substituted with oneor more substituents independently selected from the group of fluoro,—NR^(6a)R^(6b), and —OR^(6c),

R^(6a), R^(6b) and R^(6c) are each independently selected from hydrogenand C₁₋₆alkyl;

Het² is a heterocyclyl, bound through any available carbon atom,selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl,tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may beoptionally substituted with one or two substituents independentlyselected from fluoro, C₁₋₄alkyl, —OC₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkylsubstituted with one —OC₁₋₄alkyl, C₁₋₄alkyl substituted with oneC₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one or more fluorosubstituents;

Het³ is a heterocyclyl selected from the group of morpholinyl,piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl,tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may beoptionally substituted with one or two substituents independentlyselected from fluoro, C₁₋₄alkyl, —OC₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkylsubstituted with one —OC₁₋₄alkyl,

C₁₋₄alkyl substituted with one C₃₋₆cycloalkyl,

and C₁₋₄alkyl substituted with one or more fluoro substituents;

R⁸ is C₃₋₆cycloalkyl optionally substituted with one or two substituentsindependently selected from fluoro, C₁₋₄alkyl, —OC₁₋₄alkyl, C₁₋₄alkylsubstituted with one —OC₁₋₄alkyl, and C₁₋₄alkyl substituted with one ormore fluoro substituents;

R⁷ is selected from the group of hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl and

C₁₋₄alkyl substituted with one —OC₁₋₄alkyl;

and the pharmaceutically acceptable salts, and the solvates thereof.

The present invention relates in particular to compounds of Formula (I)as defined herein, and tautomers and stereoisomeric forms thereof,wherein

R¹ is C₁₋₄alkyl;

R² is selected from the group of C₁₋₄alkyl; and C₃₋₆cycloalkyl;

X is N or CR⁹;

R⁹ is halogen; in particular fluoro;

R³ is hydrogen;

R⁴ is hydrogen;

R⁵ is hydrogen;

R⁶ is selected from the group of Het²; and C₂₋₆alkyl substituted withone —OR^(6c);

R^(6c) is C₁₋₆alkyl;

Het² is a heterocyclyl, bound through any available carbon atom,selected from the group of pyrrolidinyl, and oxetanyl, each of which maybe optionally substituted with one or two substituents independentlyselected from C₁₋₄alkyl, C₃₋₆cycloalkyl, and

C₁₋₄alkyl substituted with one C₃₋₆cycloalkyl;

R⁷ is selected from the group of C₁₋₆alkyl, and C₃₋₆cycloalkyl;

and the pharmaceutically acceptable salts, and the solvates thereof.

Another embodiment of the present invention relates to those compoundsof Formula (I) and the pharmaceutically acceptable addition salts, andthe solvates thereof, or any subgroup thereof as mentioned in any of theother embodiments wherein one or more of the following restrictionsapply:

(a) R¹ is C₁₋₄alkyl;

(b) R² is selected from the group of C₁₋₄alkyl; and C₃₋₆cycloalkyl;

(c) X is N or CR⁹;

(d) R⁹ is halogen; in particular fluoro;

(e) R³ is hydrogen;

(f) R⁴ is hydrogen;

(g) R⁵ is hydrogen;

(h) R⁶ is selected from the group of Het²; and C₂₋₆alkyl substitutedwith one —OR^(6c);

(i) R^(6c) is C₁₋₆alkyl;

(j) Het² is a heterocyclyl, bound through any available carbon atom,selected from the group of pyrrolidinyl, and oxetanyl, each of which maybe optionally substituted with one or two substituents independentlyselected from C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted withone C₃₋₆cycloalkyl;

(k) R⁷ is selected from the group of C₁₋₆alkyl, and C₃₋₆cycloalkyl.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein

R¹ is selected from the group of hydrogen C₁₋₄alkyl; and C₁₋₄alkylsubstituted with one or more fluoro substituents;

R² is selected from the group of C₁₋₄alkyl; C₁₋₄alkyl substituted withone or more fluoro substituents; C₃₋₆cycloalkyl; and Het¹.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein

R¹ is selected from the group of C₁₋₄alkyl;

R² is selected from the group of C₁₋₄alkyl; C₁₋₄alkyl substituted withone or more fluoro substituents; C₃₋₆cycloalkyl; and Het¹.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein

R¹ is selected from the group of C₁₋₄alkyl;

R² is selected from the group of C₁₋₄alkyl; C₁₋₄alkyl substituted withone or more fluoro substituents; C₃₋₆cycloalkyl; and Het¹;

or R¹ and R² together with the carbon atom to which they are attachedform a C₃₋₆cycloalkyl.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein

Het¹ is a heteroaryl selected from the group of thienyl, thiazolyl,pyrrolyl, oxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, isoxazolyl, andisothiazolyl, each of which may be optionally substituted with one ortwo substituents independently selected from halogen, cyano, C₁₋₄alkyl,C₁₋₄alkyloxy, C₁₋₄alkyl substituted with one or more fluorosubstituents, and C₁₋₄alkyloxy substituted with one or more fluorosubstituents.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein X is N.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein X is N or CF.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein X is CR⁹.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein X is CF.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein

R³ is hydrogen; and R⁵is hydrogen.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein

R⁶ is Het².

In an embodiment, the present invention relates to those compounds ofFormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein

R⁶ is Het²; and

Het² is a heterocyclyl, bound through any available carbon atom,selected from the group of pyrrolidinyl, and oxetanyl, each of which maybe optionally substituted with one or two substituents independentlyselected from C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted withone C₃₋₆cycloalkyl.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein

R⁶ is C₂₋₆alkyl substituted with one —OR^(6c); and

R^(6c) is C₁₋₆alkyl.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein

R⁶ is selected from the group of Het²; and C₂₋₆alkyl substituted withone —OR^(6c).

In an embodiment, the present invention relates to those compounds ofFormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein

R⁶ is selected from the group of Het²; and C₂₋₆alkyl substituted withone —OR^(6c);

R^(6c) is C₁₋₆alkyl;

Het² is a heterocyclyl, bound through any available carbon atom,selected from the group of pyrrolidinyl, and oxetanyl, each of which maybe optionally substituted with one or two substituents independentlyselected from C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkyl substituted withone C₃₋₆cycloalkyl.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein R^(6c) is C₁₋₆alkyl; in particular methyl.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein Het³ is a heterocyclyl, bound through anyavailable carbon atom.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein

R⁶ is selected from the group of

In an embodiment, the present invention relates to those compounds ofFormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein

R⁶ is selected from the group of

In an embodiment, the present invention relates to those compounds ofFormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein R⁶ is other than hydrogen.

Specific compounds according to the invention include:

tautomers and stereoisomeric forms thereof,

and the pharmaceutically acceptable salts, and the solvates thereof.

Methods of Synthesis

Compounds of Formula (I) can be prepared by methods known to those whoare skilled in the art. The following schemes are only meant torepresent examples of the invention and are in no way meant to be alimit of the invention.

Herein, the term ‘DCM’ means dichloromethane, ‘DMF’ meansN,N-dimethylformamide, ‘NMP’ means N-methyl-2-pyrrolidone, ‘Et₃N’ meanstriethylamine, ‘TFA’ means trifluoroacetic acid and ‘[Ir(OMe)cod]₂’means (1,5-cyclooctadiene)(methoxy)iridium(I) dimer.

Scheme 1 illustrates a method of preparing compounds of Formula (I),wherein R¹-R⁷ and X are as defined in Formula (I). Intermediates ofFormula (II), wherein LG¹ is a suitable leaving group such as halogen ortriflate, can be reacted with alkynes of Formula (III) underpalladium-catalyzed Sonogashira coupling conditions, using for examplePd(PPh₃)₄, CuI and a base such as Et₃N in acetonitrile, with heating, tofurnish compounds of Formula (I).

Alkynes of Formula (III), wherein R¹ and R² are as defined in Formula(I), are commercially available or can be prepared by known methods.

Scheme 2 illustrates a further method of preparing compounds of Formula(I), wherein R¹-R⁷ and X are as defined in Formula (I). Intermediates ofFormula (IV) can be reacted with alkynes of Formula (III) underpalladium-catalysed Sonogashira coupling conditions, using for examplePd(PPh₃)₄, CuI and a base such as Et₃N in acetonitrile, with heating, tofurnish intermediates of Formula (V). Büchwald-Hartwig amination ofintermediates of Formula (V), using a suitably protected nitrogenspecies of Formula (VII) such as carbamic acid tert-butyl ester in anappropriate solvent such as 1,4-dioxane gives intermediates of Formula(VI). Removal of the protecting group under suitable conditions such asemploying TFA in DCM furnishes compounds of Formula (I).

Additional compounds of Formula (I) can be prepared by elaboration offunctional groups of compounds within the scope of this invention usingstandard chemistry. Such elaborations include, but are not limited to,hydrolysis, reduction, oxidation, alkylation, amidation and dehydration.Such transformations may in some instances require the use of protectinggroups.

Scheme 3 illustrates a method of preparing intermediates of Formula(II), wherein R³-R⁷ and X are as defined in Formula (I) and LG¹ is asdefined above. Intermediates of Formula (IV) can be reacted with3,4,5-trimethoxybenzylamine under basic conditions, for exampleemploying pyridine in a suitable solvent such as NMP with heating, toyield benzylamines of Formula (VIII). The 3,4,5-trimethoxybenzyl groupcan be removed under suitable conditions, for example employing TFA withheating to furnish intermediates of Formula (II).

Scheme 4 illustrates a method of preparing intermediates of Formula(IV), wherein R³-R⁷ and X are as defined in Formula (I) and LG¹ is asdefined above. Heating intermediates of Formula (X) with boronates ofFormula (IX) under palladium-catalyzed Suzuki coupling conditions, usingfor example Pd(PPh₃)₄, Na₂CO₃ in water and 1,4-dioxane as solvent,yields intermediates of Formula (IV).

Intermediates of Formula (X), wherein R⁷ is as defined in Formula (I),are commercially available or can be prepared by known methods (Baraldiaet al. Bioorg. Med. Chem. 2012, 20, 1046-1059).

Scheme 5 illustrates a further method for preparing intermediates ofFormula (IV), wherein R³-R⁷ and X are as defined in Formula (I) and LG¹is as defined above. Heating intermediates of Formula (X) withhexamethylditin in the presence of Pd(PPh₃)₄ yields intermediates ofFormula (XI). Intermediates of Formula (XIII) can be prepared bytreating intermediates of Formula (XII) with a mixture of iodine andpotassium hydroxide in a suitable solvent such as DMF. Heatingintermediates of Formula (XI) and (XIII) under Stille-type couplingconditions, using for example Pd(PPh₃)₄ andcopper(I)-thiophene-2-carboxylate in 1,4-dioxane as a solvent, yieldsintermediates of Formula (IV).

Scheme 6 illustrates a method of preparing intermediates of Formula(IX), wherein R³-R⁶ and X are as defined in Formula (I) and LG¹ is asdefined above. Heating of intermediates of Formula (XII) with anappropriate borane species, such as4,4,5,5-tetramethyl-1,3,2-dioxaborolane, under Iridium-catalyzedconditions using for example [Ir(OMe)cod]₂ with an appropriate ligand,such as 4,4-di-tert-butyl-2,2-dipyridyl, and cyclohexane as solventyields boronates of Formula (IX).

Scheme 7 illustrates a method of preparing intermediates of Formula(XII), wherein R³-R⁶ and X are as defined in Formula (I) and LG¹ is asdefined above. Treatment of intermediates of Formula (XIII) with asuitable electrophile under basic conditions, such as R⁶-LG² (XIV),wherein LG² is a leaving group such as halogen, mesylate or triflate,using for instance, cesium carbonate in DMF under heating, yieldsintermediates of Formula (XII).

Intermediates of Formula (XIII) and (XIV), wherein R³-R⁶ and X is asdefined in Formula (I), and LG¹ and LG² are as defined above, arecommercially available or can be prepared by known methods (Merour etal. Tet. 2013, 69, 4767-4834; Tabera et al. Tet. 2011 67, 7195-7210).

It will be appreciated that where appropriate functional groups exist,compounds of various Formulae or any intermediates used in theirpreparation may be further derivatised by one or more standard syntheticmethods employing condensation, substitution, oxidation, reduction, orcleavage reactions. Particular substitution approaches includeconventional alkylation, arylation, heteroarylation, acylation,sulfonylation, halogenation, nitration, formylation and couplingprocedures.

The compounds of Formula (I) may be synthesized in the form of racemicmixtures of enantiomers which can be separated from one anotherfollowing art-known resolution procedures. The racemic compounds ofFormula (I) containing a basic nitrogen atom may be converted into thecorresponding diastereomeric salt forms by reaction with a suitablechiral acid. Said diastereomeric salt forms are subsequently separated,for example, by selective or fractional crystallization and theenantiomers are liberated therefrom by alkali. An alternative manner ofseparating the enantiomeric forms of the compounds of Formula (I)involves liquid chromatography using a chiral stationary phase. Saidpure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically.

In the preparation of compounds of the present invention, protection ofremote functionality (e.g., primary or secondary amine) of intermediatesmay be necessary. The need for such protection will vary depending onthe nature of the remote functionality and the conditions of thepreparation methods. Suitable amino-protecting groups (NH-Pg) includeacetyl, trifluoroacetyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz)and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protectionis readily determined by one skilled in the art. For a generaldescription of protecting groups and their use, see T. W. Greene and P.G. M. Wuts, Protective Groups in Organic Synthesis, 4th ed., Wiley,Hoboken, N.J., 2007.

Compounds of the invention may be prepared from commercially availablestarting materials using the general methods illustrated herein.

Pharmacology

It has been found that the compounds of the present invention inhibitNF-κB-inducing kinase (NIK—also known as MAP3K14). The compoundsaccording to the invention and the pharmaceutical compositionscomprising such compounds may be useful for treating or preventingdiseases such as cancer, inflammatory disorders, metabolic disordersincluding obesity and diabetes, and autoimmune disorders. In particular,the compounds according to the present invention and the pharmaceuticalcompositions thereof may be useful in the treatment of a haematologicalmalignancy or solid tumour. In a specific embodiment said haematologicalmalignancy is selected from the group consisting of multiple myeloma,Hodgkin lymphoma, T-cell leukaemia, mucosa-associated lymphoid tissuelymphoma, diffuse large B-cell lymphoma and mantle cell lymphoma, in aparticular embodiment mantle cell lymphoma. In another specificembodiment of the present invention, the solid tumour is selected fromthe group consisting of pancreatic cancer, breast cancer, melanoma andnon-small cell lung cancer.

Examples of cancers which may be treated (or inhibited) include, but arenot limited to, a carcinoma, for example a carcinoma of the bladder,breast, colon (e.g. colorectal carcinomas such as colon adenocarcinomaand colon adenoma), kidney, urothelial, uterus, epidermis, liver, lung(for example adenocarcinoma, small cell lung cancer and non-small celllung carcinomas, squamous lung cancer), oesophagus, head and neck, gallbladder, ovary, pancreas (e.g. exocrine pancreatic carcinoma), stomach,gastrointestinal (also known as gastric) cancer (e.g. gastrointestinalstromal tumours), cervix, endometrium, thyroid, prostate, or skin (forexample squamous cell carcinoma or dermatofibrosarcoma protuberans);pituitary cancer, a hematopoietic tumour of lymphoid lineage, forexample leukemia, acute lymphocytic leukemia, chronic lymphocyticleukemia, B-cell lymphoma (e.g. diffuse large B-cell lymphoma, mantlecell lymphoma), T-cell leukaemia/lymphoma, Hodgkin's lymphoma,non-Hodgkin's lymphoma, hairy cell lymphoma, or Burkett's lymphoma; ahematopoietic tumour of myeloid lineage, for example leukemias, acuteand chronic myelogenous leukemias, chronic myelomonocytic leukemia(CMML), myeloproliferative disorder, myeloproliferative syndrome,myelodysplastic syndrome, or promyelocytic leukemia; multiple myeloma;thyroid follicular cancer; hepatocellular cancer, a tumour ofmesenchymal origin (e.g. Ewing's sarcoma), for example fibrosarcoma orrhabdomyosarcoma; a tumour of the central or peripheral nervous system,for example astrocytoma, neuroblastoma, glioma (such as glioblastomamultiforme) or schwannoma; melanoma; seminoma; teratocarcinoma;osteosarcoma; xeroderma pigmentosum; keratoctanthoma; thyroid follicularcancer; or Kaposi's sarcoma.

Hence, the invention relates to compounds of Formula (I), the tautomersand the stereoisomeric forms thereof, and the pharmaceuticallyacceptable salts, and the solvates thereof, for use as a medicament.

The invention also relates to the use of a compound of Formula (I), or atautomer or a stereoisomeric form thereof, or a pharmaceuticallyacceptable salt, or a solvate thereof, or a pharmaceutical compositionaccording to the invention, for the manufacture of a medicament.

The present invention also relates to a compound of Formula (I), or atautomer or a stereoisomeric form thereof, or a pharmaceuticallyacceptable salt, or a solvate thereof, or a pharmaceutical compositionaccording to the invention, for use in the treatment, prevention,amelioration, control or reduction of the risk of disorders associatedwith NF-κB-inducing kinase dysfunction in a mammal, including a human,the treatment or prevention of which is affected or facilitated byinhibition of NF-κB-inducing kinase. Also, the present invention relatesto the use of a compound of Formula (I), or a tautomer or astereoisomeric form thereof, or a pharmaceutically acceptable salt, or asolvate thereof, or a pharmaceutical composition according to theinvention, for the manufacture of a medicament for treating, preventing,ameliorating, controlling or reducing the risk of disorders associatedwith NF-κB-inducing kinase dysfunction in a mammal, including a human,the treatment or prevention of which is affected or facilitated byinhibition of NF-κB-inducing kinase.

The invention also relates to a compound of Formula (I), or a tautomeror a stereoisomeric form thereof, or a pharmaceutically acceptable salt,or a solvate thereof, for use in the treatment or prevention of any oneof the diseases mentioned hereinbefore.

The invention also relates to a compound of Formula (I), or a tautomeror a stereoisomeric form thereof, or a pharmaceutically acceptable salt,or a solvate thereof, for use in treating or preventing any one of thediseases mentioned hereinbefore.

The invention also relates to the use of a compound of Formula (I), or atautomer or a stereoisomeric form thereof, or a pharmaceuticallyacceptable salt, or a solvate thereof, for the manufacture of amedicament for the treatment or prevention of any one of the diseaseconditions mentioned hereinbefore.

The compounds of the present invention can be administered to mammals,preferably humans, for the treatment or prevention of any one of thediseases mentioned hereinbefore.

In view of the utility of the compounds of Formula (I), or a tautomer ora stereoisomeric form thereof, or a pharmaceutically acceptable salt, ora solvate thereof, there is provided a method of treating warm-bloodedanimals, including humans, suffering from any one of the diseasesmentioned hereinbefore.

Said method comprises the administration, i.e. the systemic or topicaladministration, preferably oral administration, of a therapeuticallyeffective amount of a compound of Formula (I), or a tautomer or astereoisomeric form thereof, or a pharmaceutically acceptable salt, or asolvate thereof, to warm-blooded animals, including humans.

Therefore, the invention also relates to a method for the treatment ofany one of the diseases mentioned hereinbefore comprising administeringa therapeutically effective amount of compound according to theinvention to a patient in need thereof.

One skilled in the art will recognize that a therapeutically effectiveamount of the compounds of the present invention is the amountsufficient to have therapeutic activity and that this amount variesinter alias, depending on the type of disease, the concentration of thecompound in the therapeutic formulation, and the condition of thepatient. Generally, the amount of a compound of the present invention tobe administered as a therapeutic agent for treating the disordersreferred to herein will be determined on a case by case by an attendingphysician.

Those of skill in the treatment of such diseases could determine theeffective therapeutic daily amount from the test results presentedhereinafter. An effective therapeutic daily amount would be from about0.005 mg/kg to 50 mg/kg, in particular 0.01 mg/kg to 50 mg/kg bodyweight, more in particular from 0.01 mg/kg to 25 mg/kg body weight,preferably from about 0.01 mg/kg to about 15 mg/kg, more preferably fromabout 0.01 mg/kg to about 10 mg/kg, even more preferably from about 0.01mg/kg to about 1 mg/kg, most preferably from about 0.05 mg/kg to about 1mg/kg body weight. The amount of a compound according to the presentinvention, also referred to here as the active ingredient, which isrequired to achieve a therapeutically effect may vary on case-by-casebasis, for example with the particular compound, the route ofadministration, the age and condition of the recipient, and theparticular disorder or disease being treated. A method of treatment mayalso include administering the active ingredient on a regimen of betweenone and four intakes per day. In these methods of treatment thecompounds according to the invention are preferably formulated prior toadministration. As described herein below, suitable pharmaceuticalformulations are prepared by known procedures using well known andreadily available ingredients.

The present invention also provides compositions for preventing ortreating the disorders referred to herein. Said compositions comprisinga therapeutically effective amount of a compound of Formula (I), or atautomer or a stereoisomeric form thereof, or a pharmaceuticallyacceptable salt, or a solvate thereof, and a pharmaceutically acceptablecarrier or diluent.

While it is possible for the active ingredient to be administered alone,it is preferable to present it as a pharmaceutical composition.Accordingly, the present invention further provides a pharmaceuticalcomposition comprising a compound according to the present invention,together with a pharmaceutically acceptable carrier or diluent. Thecarrier or diluent must be “acceptable” in the sense of being compatiblewith the other ingredients of the composition and not deleterious to therecipients thereof.

The pharmaceutical compositions of this invention may be prepared by anymethods well known in the art of pharmacy, for example, using methodssuch as those described in Gennaro et al. Remington's PharmaceuticalSciences (18t^(h) ed., Mack Publishing Company, 1990, see especiallyPart 8: Pharmaceutical preparations and their Manufacture). Atherapeutically effective amount of the particular compound, in baseform or addition salt form, as the active ingredient is combined inintimate admixture with a pharmaceutically acceptable carrier, which maytake a wide variety of forms depending on the form of preparationdesired for administration. These pharmaceutical compositions aredesirably in unitary dosage form suitable, preferably, for systemicadministration such as oral, percutaneous or parenteral administration;or topical administration such as via inhalation, a nose spray, eyedrops or via a cream, gel, shampoo or the like. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed, such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs and solutions: orsolid carriers such as starches, sugars, kaolin, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules and tablets. Because of their ease in administration, tabletsand capsules represent the most advantageous oral dosage unit form, inwhich case solid pharmaceutical carriers are obviously employed. Forparenteral compositions, the carrier will usually comprise sterilewater, at least in large part, though other ingredients, for example, toaid solubility, may be included. Injectable solutions, for example, maybe prepared in which the carrier comprises saline solution, glucosesolution or a mixture of saline and glucose solution. Injectablesuspensions may also be prepared in which case appropriate liquidcarriers, suspending agents and the like may be employed. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewettable agent, optionally combined with suitable additives of anynature in minor proportions, which additives do not cause anysignificant deleterious effects on the skin. Said additives mayfacilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as a spot-onor as an ointment.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

The present compounds can be used for systemic administration such asoral, percutaneous or parenteral administration; or topicaladministration such as via inhalation, a nose spray, eye drops or via acream, gel, shampoo or the like. The compounds are preferably orallyadministered. The exact dosage and frequency of administration dependson the particular compound of Formula (I) used, the particular conditionbeing treated, the severity of the condition being treated, the age,weight, sex, extent of disorder and general physical condition of theparticular patient as well as other medication the individual may betaking, as is well known to those skilled in the art. Furthermore, it isevident that said effective daily amount may be lowered or increaseddepending on the response of the treated subject and/or depending on theevaluation of the physician prescribing the compounds of the instantinvention.

The compounds of the present invention may be administered alone or incombination with one or more additional therapeutic agents. Combinationtherapy includes administration of a single pharmaceutical dosageformulation which contains a compound according to the present inventionand one or more additional therapeutic agents, as well as administrationof the compound according to the present invention and each additionaltherapeutic agent in its own separate pharmaceutical dosage formulation.For example, a compound according to the present invention and atherapeutic agent may be administered to the patient together in asingle oral dosage composition such as a tablet or capsule, or eachagent may be administered in separate oral dosage formulations.

For the treatment of the above conditions, the compounds of theinvention may be advantageously employed in combination with one or moreother medicinal agents, more particularly, with other anti-cancer agentsor adjuvants in cancer therapy. Examples of anti-cancer agents oradjuvants (supporting agents in the therapy) include but are not limitedto:

-   -   platinum coordination compounds for example cisplatin optionally        combined with amifostine, carboplatin or oxaliplatin;    -   taxane compounds for example paclitaxel, paclitaxel protein        bound particles (Abraxane™) or docetaxel;    -   topoisomerase I inhibitors such as camptothecin compounds for        example irinotecan, SN-38, topotecan, topotecan hcl;    -   topoisomerase II inhibitors such as anti-tumour        epipodophyllotoxins or podophyllotoxin derivatives for example        etoposide, etoposide phosphate or teniposide;    -   anti-tumour vinca alkaloids for example vinblastine, vincristine        or vinorelbine;    -   anti-tumour nucleoside derivatives for example 5-fluorouracil,        leucovorin, gemcitabine, gemcitabine hcl, capecitabine,        cladribine, fludarabine, nelarabine;    -   alkylating agents such as nitrogen mustard or nitrosourea for        example cyclophosphamide, chlorambucil, carmustine, thiotepa,        mephalan (melphalan), lomustine, altretamine, busulfan,        dacarbazine, estramustine, ifosfamide optionally in combination        with mesna, pipobroman, procarbazine, streptozocin,        temozolomide, uracil;    -   anti-tumour anthracycline derivatives for example daunorubicin,        doxorubicin optionally in combination with dexrazoxane, doxil,        idarubicin, mitoxantrone, epirubicin, epirubicin hcl,        valrubicin;    -   molecules that target the IGF-1 receptor for example        picropodophilin;    -   tetracarcin derivatives for example tetrocarcin A;    -   glucocorticoïden for example prednisone; -    -   antibodies for example trastuzumab (HER2 antibody), rituximab        (CD20 antibody), gemtuzumab, gemtuzumab ozogamicin, cetuximab,        pertuzumab, bevacizumab, alemtuzumab, eculizumab, ibritumomab        tiuxetan, nofetumomab, panitumumab, tositumomab, CNTO 328;    -   estrogen receptor antagonists or selective estrogen receptor        modulators or inhibitors of estrogen synthesis for example        tamoxifen, fulvestrant, toremifene, droloxifene, faslodex,        raloxifene or letrozole;    -   aromatase inhibitors such as exemestane, anastrozole, letrazole,        testolactone and vorozole;    -   differentiating agents such as retinoids, vitamin D or retinoic        acid and retinoic acid metabolism blocking agents (RAMBA) for        example accutane;    -   DNA methyl transferase inhibitors for example azacytidine or        decitabine;    -   antifolates for example premetrexed disodium;    -   antibiotics for example antinomycin D, bleomycin, mitomycin C,        dactinomycin, carminomycin, daunomycin, levamisole, plicamycin,        mithramycin;    -   antimetabolites for example clofarabine, aminopterin, cytosine        arabinoside or methotrexate, azacitidine, cytarabine,        floxuridine, pentostatin, thioguanine;    -   apoptosis inducing agents and antiangiogenic agents such as        Bcl-2 inhibitors for example YC 137, BH 312, ABT 737, gossypol,        HA 14-1, TW 37 or decanoic acid;    -   tubuline-binding agents for example combrestatin, colchicines or        nocodazole;    -   kinase inhibitors (e.g. EGFR (epithelial growth factor receptor)        inhibitors, MTKI (multi target kinase inhibitors), mTOR        inhibitors) for example flavoperidol, imatinib mesylate,        erlotinib, gefitinib, dasatinib, lapatinib, lapatinib        ditosylate, sorafenib, sunitinib, sunitinib maleate,        temsirolimus;    -   farnesyltransferase inhibitors for example tipifarnib;    -   histone deacetylase (HDAC) inhibitors for example sodium        butyrate, suberoylanilide hydroxamic acid (SAHA), depsipeptide        (FR 901228), NVP-LAQ824, R306465, quisinostat, trichostatin A,        vorinostat;    -   Inhibitors of the ubiquitin-proteasome pathway for example        PS-341, MLN.41 or bortezomib;    -   Yondelis;    -   Telomerase inhibitors for example telomestatin;    -   Matrix metalloproteinase inhibitors for example batimastat,        marimastat, prinostat or metastat;    -   Recombinant interleukins for example aldesleukin, denileukin        diftitox, interferon alfa 2a, interferon alfa 2b, peginterferon        alfa 2b;    -   MAPK inhibitors;    -   Retinoids for example alitretinoin, bexarotene, tretinoin;    -   Arsenic trioxide;    -   Asparaginase;    -   Steroids for example dromostanolone propionate, megestrol        acetate, nandrolone (decanoate, phenpropionate), dexamethasone;    -   Gonadotropin releasing hormone agonists or antagonists for        example abarelix, goserelin acetate, histrelin acetate,        leuprolide acetate;    -   Thalidomide, lenalidomide;    -   Mercaptopurine, mitotane, pamidronate, pegademase, pegaspargase,        rasburicase;    -   BH3 mimetics for example ABT-737;    -   MEK inhibitors for example PD98059, AZD6244, CI-1040;    -   colony-stimulating factor analogs for example filgrastim,        pegfilgrastim, sargramostim; erythropoietin or analogues thereof        (e.g. darbepoetin alfa); interleukin 11; oprelvekin;        zoledronate, zoledronic acid; fentanyl; bisphosphonate;        palifermin;    -   a steroidal cytochrome P450 17alpha-hydroxylase-17,20-lyase        inhibitor (CYP17), e.g. abiraterone, abiraterone acetate.

Therefore, an embodiment of the present invention relates to a productcontaining as first active ingredient a compound according to theinvention and as further active ingredient one or more anticancer agent,as a combined preparation for simultaneous, separate or sequential usein the treatment of patients suffering from cancer.

The one or more other medicinal agents and the compound according to thepresent invention may be administered simultaneously (e.g. in separateor unitary compositions) or sequentially in either order. In the lattercase, the two or more compounds will be administered within a period andin an amount and manner that is sufficient to ensure that anadvantageous or synergistic effect is achieved. It will be appreciatedthat the preferred method and order of administration and the respectivedosage amounts and regimes for each component of the combination willdepend on the particular other medicinal agent and compound of thepresent invention being administered, their route of administration, theparticular tumour being treated and the particular host being treated.The optimum method and order of administration and the dosage amountsand regime can be readily determined by those skilled in the art usingconventional methods and in view of the information set out herein.

The weight ratio of the compound according to the present invention andthe one or more other anticancer agent(s) when given as a combinationmay be determined by the person skilled in the art. Said ratio and theexact dosage and frequency of administration depends on the particularcompound according to the invention and the other anticancer agent(s)used, the particular condition being treated, the severity of thecondition being treated, the age, weight, gender, diet, time ofadministration and general physical condition of the particular patient,the mode of administration as well as other medication the individualmay be taking, as is well known to those skilled in the art.Furthermore, it is evident that the effective daily amount may belowered or increased depending on the response of the treated subjectand/or depending on the evaluation of the physician prescribing thecompounds of the instant invention. A particular weight ratio for thepresent compound of Formula (I) and another anticancer agent may rangefrom 1/10 to 10/1, more in particular from 1/5 to 5/1, even more inparticular from 1/3 to 3/1.

The platinum coordination compound is advantageously administered in adosage of 1 to 500 mg per square meter (mg/m2) of body surface area, forexample 50 to 400 mg/m2, particularly for cisplatin in a dosage of about75 mg/m2 and for carboplatin in about 300 mg/m2 per course of treatment.

The taxane compound is advantageously administered in a dosage of 50 to400 mg per square meter (mg/m2) of body surface area, for example 75 to250 mg/m2, particularly for paclitaxel in a dosage of about 175 to 250mg/m2 and for docetaxel in about 75 to 150 mg/m2 per course oftreatment.

The camptothecin compound is advantageously administered in a dosage of0.1 to 400 mg per square meter (mg/m2) of body surface area, for example1 to 300 mg/m2, particularly for irinotecan in a dosage of about 100 to350 mg/m2 and for topotecan in about 1 to 2 mg/m2 per course oftreatment.

The anti-tumour podophyllotoxin derivative is advantageouslyadministered in a dosage of 30 to 300 mg per square meter (mg/m2) ofbody surface area, for example 50 to 250 mg/m2, particularly foretoposide in a dosage of about 35 to 100 mg/m2 and for teniposide inabout 50 to 250 mg/m2 per course of treatment.

The anti-tumour vinca alkaloid is advantageously administered in adosage of 2 to 30 mg per square meter (mg/m2) of body surface area,particularly for vinblastine in a dosage of about 3 to 12 mg/m2, forvincristine in a dosage of about 1 to 2 mg/m2, and for vinorelbine indosage of about 10 to 30 mg/m2 per course of treatment.

The anti-tumour nucleoside derivative is advantageously administered ina dosage of 200 to 2500 mg per square meter (mg/m2) of body surfacearea, for example 700 to 1500 mg/m2, particularly for 5-FU in a dosageof 200 to 500mg/m2, for gemcitabine in a dosage of about 800 to 1200mg/m2 and for capecitabine in about 1000 to 2500 mg/m2 per course oftreatment.

The alkylating agents such as nitrogen mustard or nitrosourea isadvantageously administered in a dosage of 100 to 500 mg per squaremeter (mg/m2) of body surface area, for example 120 to 200 mg/m2,particularly for cyclophosphamide in a dosage of about 100 to 500 mg/m2,for chlorambucil in a dosage of about 0.1 to 0.2 mg/kg, for carmustinein a dosage of about 150 to 200 mg/m2, and for lomustine in a dosage ofabout 100 to 150 mg/m2 per course of treatment.

The anti-tumour anthracycline derivative is advantageously administeredin a dosage of 10 to 75 mg per square meter (mg/m2) of body surfacearea, for example 15 to 60 mg/m2, particularly for doxorubicin in adosage of about 40 to 75 mg/m2, for daunorubicin in a dosage of about 25to 45mg/m2, and for idarubicin in a dosage of about 10 to 15 mg/m2 percourse of treatment.

The antiestrogen agent is advantageously administered in a dosage ofabout 1 to 100 mg daily depending on the particular agent and thecondition being treated. Tamoxifen is advantageously administered orallyin a dosage of 5 to 50 mg, preferably 10 to 20 mg twice a day,continuing the therapy for sufficient time to achieve and maintain atherapeutic effect. Toremifene is advantageously administered orally ina dosage of about 60 mg once a day, continuing the therapy forsufficient time to achieve and maintain a therapeutic effect.Anastrozole is advantageously administered orally in a dosage of about 1mg once a day. Droloxifene is advantageously administered orally in adosage of about 20-100 mg once a day. Raloxifene is advantageouslyadministered orally in a dosage of about 60 mg once a day. Exemestane isadvantageously administered orally in a dosage of about 25 mg once aday.

Antibodies are advantageously administered in a dosage of about 1 to 5mg per square meter (mg/m2) of body surface area, or as known in theart, if different. Trastuzumab is advantageously administered in adosage of 1 to 5 mg per square meter (mg/m2) of body surface area,particularly 2 to 4 mg/m2 per course of treatment.

These dosages may be administered for example once, twice or more percourse of treatment, which may be repeated for example every 7, 14, 21or 28 days.

The following examples further illustrate the present invention.

EXAMPLES

Several methods for preparing the compounds of this invention areillustrated in the following examples. Unless otherwise noted, allstarting materials were obtained from commercial suppliers and usedwithout further purification.

Herein, the term ‘Cs₂CO₃’ means cesium carbonate, ‘Et₃N’ meanstriethylamine, ‘DCM’ means dichloromethane, ‘BEH’ means bridgedethylsiloxane/silica hybrid, ‘DIPEA’ means diisopropylethylamine, ‘DMAP’means N,N-dimethylpyridin-4-amine, ‘DMF’ means N,N-dimethylformamide,‘Celite®’ means diatomaceous earth, ‘DMSO’ means dimethylsulfoxide,‘UPLC’ means ultra performance liquid chromatography, ‘LC’ means liquidchromatography, ‘EtOAc’ means ethyl acetate, ‘HPLC’ means highperformance liquid chromatography, ‘LCMS’ means liquidchromatography/mass spectrometry, ‘MeCN’ means acetonitrile, ‘MeOH’means methanol, ‘Na₂SO₄’ means sodium sulfate, ‘NMP’ meansN-methylpyrrolidinone, ‘R_(t)’ means retention time, ‘ISOLUTE® SCX-2SPE’ means ISOLUTE® silica propylsulfonic acid strong cation exchangecolumn, ‘TBAF’ means tetrabutylammonium fluoride, ‘TFA’ meanstrifluoroacetic acid and ‘THF’ means tetrahydrofuran, ‘Et₂O’ meansdiethyl ether, ‘Xantphos’ means[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate.

In the structures of the intermediates and the compounds of the presentinvention, deuterium (²H) is represented by the chemical symbol D.

When in the Examples below, intermediates or compounds were preparedaccording to the reaction protocol of a fully described Example, thismeans that the intermediate or compound was prepared by an analogousreaction protocol (but not necessarily identical) as the Examplereferred to.

Preparation of Intermediates

Example A1

a) Preparation of Intermediate 1

A stirred solution of (methyldiphenylsilyl)acetylene (4.95 ml, 22.5mmol) in anhydrous THF (80 ml) under an argon atmosphere at −78° C. wastreated with a 1.6 M solution of n-butyllithium in hexanes (15.5 ml,24.8 mmol) maintaining the temperature below −70° C. After 1 hour, themixture was treated with acetone-d₆ (1.95 ml, 27.0 mmol) and theresulting mixture stirred at 0° C. for 1.5 hours. The mixture wasquenched by the addition of water and partitioned between water andEtOAc. The organic phase was washed with brine, dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel, eluting with a mixture of EtOAc and cyclohexane (0:1 to2:3 by volume), to afford the desired product as a colourless oil (6.31g, 98%).

Example A2

a) Preparation of Intermediate 2

A stirred solution of 5-bromo-1H-pyrrolo[2,3-c]pyridine (2.22 g, 11.3mmol) in DMF (30 ml) at ambient temperature was treated with potassiumhydroxide (2.53 g, 45.1 mmol). After 10 minutes, iodine (3.15 g, 12.4mmol) was added and the resulting mixture was stirred for 2 hours. Themixture was diluted with water and extracted with EtOAc. The combinedorganic extracts were washed with brine, dried over Na₂SO₄ andconcentrated in vacuo. The residue was triturated with water to affordthe desired product as an orange solid (3.39 g, 93%).

LCMS (Method C): R_(t)=3.14 min, m/z [M+H]⁺=323/325.

b) Preparation of Intermediate 3

A stirred suspension of intermediate 2 (3.39 g, 10.5 mmol) in DCM (60ml) at 0° C. was treated sequentially with DMAP (0.128 g, 1.05 mmol),DIPEA (3.66 ml, 21.0 mmol) and di-tert-butyldicarbonate (3.44 g, 15.7mmol). The resulting mixture was warmed to ambient temperature andstirred for 1 hour. The mixture was concentrated in vacuo andtrituration of the residue with water afforded the desired product as apale yellow solid (4.24 g, 96%).

LCMS (Method C): R_(t)=4.58 min, m/z [M+H]⁺=423/425.

c) Preparation of Intermediate 4

A degassed mixture of 5,7-dichloro-2-methyl-2H-pyrazolo[4,3-d]pyrimidine(0.10 g, 0.49 mmol), hexamethylditin (0.18 g, 0.54 mmol),tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.024 mmol) and1,4-dioxane (2.0 ml) under an argon atmosphere was heated at 80° C. for1 hour. The reaction mixture was cooled to ambient temperature, treatedwith a degassed mixture of tetrakis(triphenylphosphine)palladium(0)(0.03 g, 0.024 mmol), intermediate 3(0.21 g, 0.49 mmol), copperthiophene carboxylate (0.009 g, 0.05 mmol) and 1,4-dioxane (2.0 ml), andthe resulting mixture was heated at 80° C. for 18 hours. The mixture wascooled to ambient temperature and concentrated in vacuo. Trituration ofthe residue with Et₂O afforded the desired compound as a yellow solid(0.14 g, 62%).

LCMS (Method C): R_(t)=4.59 min, m/z [M+H]⁺=463/465/467.

d) Preparation of Intermediate 5

A stirred solution of intermediate 4 (0.74 g, 1.59 mmol) in DCM (10 ml)under a nitrogen atmosphere at 5° C. was treated with TFA (3.0 ml, 39.0mmol), and the resulting mixture was stirred at ambient temperature for3 hours. The mixture was concentrated in vacuo and trituration of theresidue with Et₂O afforded the desired product as a pale yellow solid(0.80 g, 100%).

LCMS (Method C): R_(t)=3.12 min, m/z [M+H]⁺=363/365/367.

e) Preparation of Intermediate 6

A stirred mixture of intermediate 5 (0.40 g, 1.1 mmol),1-bromo-3-methoxypropane (0.08 ml, 0.55 mmol), Cs₂CO₃ (0.72 g, 2.20mmol) and DMF (4.0 ml) was heated by microwave irradiation at 110° C.for 1 hour. The mixture was cooled to ambient temperature andconcentrated in vacuo. Trituration of the residue with Et₂O afforded asolid. The solid was collected by filtration and washed sequentiallywith water and acetone to afford the desired product as a brown solid(0.32 g, 66%).

LCMS (Method B): R_(t)=3.54 min, m/z [M+H]⁺=435/437/439.

f) Preparation of Intermediate 7

A stirred mixture of intermediate 6 (0.28 g, 0.64 mmol),3,4,5-trimethoxybenzylamine (0.63 g, 3.19 mmol), pyridine (0.51 g, 6.32mmol) and NMP (4.0 ml) was heated by microwave irradiation at 185° C.for 2 hours. The mixture was cooled to ambient temperature and purifiedby ISOLUTE® SCX-2 SPE column eluting with a mixture of MeOH and 2.0 Mammonia solution in MeOH (1:0 to 0:1 by volume). Further purification bycolumn chromatography on silica gel, eluting with a mixture of MeOH andDCM (0:1 to 1:9 by volume), afforded the desired product as a paleyellow solid (0.15 g, 39%).

LCMS (Method B): R_(t)=2.45 min, m/z [M+H]⁺=596/598.

g) Preparation of Intermediate 8

A stirred mixture of intermediate 7 (0.14 g, 0.24 mmol) and TFA (1.0 ml,13.1 mmol) under a nitrogen atmosphere was heated at reflux for 72hours. The mixture was cooled to ambient temperature and concentrated invacuo. The residue was purified by ISOLUTE® SCX-2 SPE column elutingwith a mixture of MeOH and 2.0 M ammonia solution in MeOH (1:0 to 0:1 byvolume). Further purification by column chromatography on silica gel,eluting with a mixture of 2.0 M ammonia solution in MeOH and DCM (0:1 to1:9 by volume), followed by trituration with Et₂O afforded the desiredproduct as a brown solid (0.04 g, 45%).

LCMS (Method B): R_(t)=1.79 and 1.98 min, m/z [M+H]⁺=416/418.

Example A3

a) Preparation of Intermediate 9

A degassed mixture of 5-bromo-pyrrolo[2,3-c]pyridine-1-carboxylic acidtert-butyl ester (50.0 g, 168 mmol), 4,4,-di-tert-butyl-2,2-dipyridyl(0.90 g, 3.37 mmol) and cyclohexane (500 ml) under an argon atmosphereat ambient temperature was treated sequentially withdi-μ-methoxobis(1,5-cyclooctadiene)diiridium (1.12 g, 1.68 mmol) and4,4,5,5-tetramethyl-1,3,2-dioxaborolane (122 ml, 841 mmol), and theresulting mixture was stirred at 60° C. for 5 hours. The mixture wascooled to ambient temperature and concentrated in vacuo. The residue waspurified by column chromatography on silica gel, eluting with a mixtureof EtOAc and pentane (0:1 to 1:1 by volume), to afford the desiredproduct as a white solid (50.0 g, 70%).

LCMS (Method B): R_(t)=4.78 min, m/z [M+H]⁺=423/425.

b) Preparation of Intermediate 10

A degassed mixture of intermediate 9 (1.16 g, 2.75 mmol),5,7-dichloro-2-cyclopropyl-2H-pyrazolo[4,3-d]pyrimidine (0.42 g, 1.83mmol), tetrakis(triphenylphosphine)palladium (0.11 g, 0.09 mmol), sodiumcarbonate (0.58 mg, 5.5 mmol), 1,4-dioxane (9.0 ml) and water (3.0 ml)was stirred under an argon atmosphere at 100° C. for 5 hours. Themixture was cooled to ambient temperature and poured onto MeOH (30 ml).The resulting solid was collected by filtration and washed sequentiallywith water and Et₂O. The solid was treated with TFA (7.0 ml), and theresulting mixture stirred at ambient temperature for 1 hour. The mixturewas concentrated in vacuo to afford the desired product (0.92 g, 100%).

LCMS (Method B): R_(t)=3.46 min, m/z [M+H]⁺=389/391/393.

c) Preparation of Intermediate 11

A stirred mixture of intermediate 10 (0.92 g, 1.84 mmol),1-bromo-3-methoxypropane (0.35 g, 2.29 mmol), Cs₂CO₃ (2.39 g, 7.33 mmol)and DMF (10 ml) was heated by microwave irradiation at 110° C. for 2.0hours. The mixture was cooled to ambient temperature and partitionedbetween water and EtOAc. The organic phase was dried over Na₂SO₄ andconcentrated in vacuo. Trituration of the residue with Et₂O afforded thedesired product as a pale yellow solid (0.57 g, 67%).

LCMS (Method B): R_(t)=4.02 min, m/z [M+H]⁺=461/463/465.

d) Preparation of Intermediate 12

A stirred mixture of intermediate 11 (0.55 g, 1.19 mmol),2-cyclopropyl-but-3-yn-2-ol (0.16 g, 1.43 mmol),tetrakis(triphenylphosphine) palladium (0.14 g, 0.12 mmol), copper(I)iodide (13.3 mg, 0.07 mmol), Et₃N (0.60 ml, 5.95 mmol) and MeCN (8.0 ml)was heated by microwave irradiation at 90° C. for 1 hour. The mixturewas cooled to ambient temperature and concentrated in vacuo. The residuewas purified by column chromatography on silica gel, eluting with amixture of MeOH and DCM (0:1 to 1:9 by volume), to afford the desiredproduct as a pale yellow solid (0.22 g, 0.44 mmol).

LCMS (Method B): R_(t)=3.16 min, m/z [M+H]⁺=491/493.

Intermediate 13 was prepared by an analogous reaction protocol asintermediate 10 using the appropriate starting materials (Table 1).

TABLE 1 Intermediate Structure Starting Materials LCMS Data 13

a) Intermediate 9 b) 5,7-Dichloro-2- ethyl-2H- pyrazolo[4,3-d]pyrimidine R_(t) = 3.35 min, m/z [M + H]⁺ = 377/379/381 (Method C)

Intermediate 14 was prepared by an analogous reaction protocol asintermediate 11 using the appropriate starting materials (Table 2).

TABLE 2 Intermediate Structure Starting Materials LCMS Data 14

a) Intermediate 13 b) 1-Bromo-3- methoxypropane R_(t) = 3.80 min, m/z[M + H]⁺ = 449/451/453 (Method B)

Intermediates 15 to 18 were prepared by an analogous reaction protocolas intermediate 12 using the appropriate starting materials (Table 3).

TABLE 3 Intermediate Structure Starting Materials LCMS Data 15

a) Intermediate 14 b) 2-Cyclopropyl- but-3-yn-2-ol R_(t) = 3.03 min, m/z[M + H]⁺ = 479/481 (Method B) 16

a) Intermediate 36 b) 2-Cyclopropyl- but-3-yn-2-ol R_(t) = 2.36 min, m/z[M + H]⁺ = 502/504 (Method B) 17

a) Intermediate 43 b) 1,1,1- Trideutero-2- trideuteromethyl-3-butyn-2-ol R_(t) = 2.23 min, m/z [M + H]⁺ = 496/498 (Method C) 18

a) Intermediate 36 b) 1,1,1- Trideutero-2- trideuteromethyl-3-butyn-2-ol R_(t) = 2.20 min, m/z [M + H]⁺ = 482/484 (Method C)

Example A4

a) Preparation of Intermediate 19

A stirred solution of 5-bromo-6-fluoro-1H-indole (2.5 g, 11.7 mmol) inDMF (30 ml) at ambient temperature was treated with potassium hydroxide(2.5 g, 44.6 mmol). After 10 minutes, iodine (4.45 g, 17.5 mmol) wasadded and the resulting mixture was stirred for 18 hours. The mixturewas diluted with water and extracted with EtOAc. The combined extractswere washed with 5% aqueous sodium metabisulfite solution and brine,dried over Na₂SO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel, eluting with a mixture of EtOAc andcyclohexane (0:1 to 2:3 by volume), to afford the desired product as anoff-white solid (1.88 g, 47%).

LCMS (Method B): R_(t)=3.94 min, m/z [M−H]³¹ =338/340.

b) Preparation of Intermediate 20

A mixture of intermediate 19 (29.4 g, 86.7 mmol),4-methylbenzenesulfonyl chloride (16.5 g, 86.7 mmol), sodium hydroxide(6.8 g, 152 mmol), benzyltriethylammonium chloride (1.64 g, 8.67 mmol)and anhydrous DCM (52 ml) was stirred at 0° C. for 1 hour and then atambient temperature for 2 hours. The mixture was partitioned betweenwater and EtOAc. The organic phase was washed with brine, dried overNa₂SO₄ and concentrated in vacuo. The residue was purified bycrystallisation from a mixture of EtOAc and petroleum ether (1:1 byvolume) to afford the desired product as a white solid (20 g, 47%).

Example A5

a) Preparation of Intermediate 21

A degassed mixture of 5,7-dichloro-2-ethyl-2H-pyrazolo[4,3-d]pyrimidine(0.10 g, 0.46 mmol), hexamethylditin (0.30 g, 0.92 mmol),tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.023 mmol) and1,4-dioxane (6.0 ml) under an argon atmosphere was heated at 80° C. for7 hours. The mixture was cooled to ambient temperature, filtered throughCelite® and the filtrate concentrated in vacuo to afford the desiredproduct as a brown solid (0.17 g, 100%).

LCMS (Method B): R_(t)=3.76 min, m/z [M+H]⁺=345/347.

b) Preparation of Intermediate 22

A degassed mixture of intermediate 20 (0.23 g, 0.47 mmol), intermediate21 (0.16 g, 0.47 mmol), tetrakis(triphenylphosphine)palladium(0) (0.03g, 0.023 mmol), copper thiophene carboxylate (0.009 g, 0.046 mmol) and1,4-dioxane (3.0 ml) was heated at 85° C. for 18 hours. The mixture wascooled to ambient temperature and concentrated in vacuo. Trituration ofthe residue with Et₂O afforded the desired product as a light brownsolid (0.26 g, 100%).

LCMS (Method B): R_(t)=4.98 min, m/z [M+H]⁺=548/550/552.

c) Preparation of Intermediate 23

A stirred solution of intermediate 22 (0.35 g, 0.64 mmol) in a mixtureof THF (10 ml) and MeOH (30 ml) at ambient temperature was treated withsodium methoxide (25% wt. in MeOH, 1.46 ml, 6.4 mmol), and the resultingmixture was stirred for 45 minutes. The mixture was concentrated invacuo and the residue partitioned between EtOAc and a saturated aqueoussodium hydrogen carbonate solution. The organic phase was washed withbrine, dried over Na₂SO₄ and concentrated in vacuo. Trituration of theresidue with Et₂O afforded the desired product as a yellow solid (0.21g, 82%).

LCMS (Method B): R_(t)=3.95 min, m/z [M+H]⁺=394/396/398.

d) Preparation of Intermediate 24

A stirred solution of intermediate 23 (0.21 g, 0.53 mmol) in DMF (4.0ml) at ambient temperature was treated with sodium hydride (60% inmineral oil, 0.023 g, 0.58 mmol). After 5 minutes, the mixture wastreated with 1-bromo-3-methoxypropane (0.09 g, 0.58 mmol) and theresulting mixture was stirred at 50° C. for 2.0 hours. The mixture wascooled to ambient temperature and partitioned between EtOAc and brine.The organic phase was dried over Na₂SO₄ and concentrated in vacuo.Trituration of the residue with Et₂O afforded the desired product as ayellow solid (0.21 g, 88%).

LCMS (Method B): R_(t)=4.43 min, m/z [M+H]⁺=466/468/470.

e) Preparation of Intermediate 25

A stirred mixture of intermediate 24 (0.62 g, 1.32 mmol),3,4,5-trimethoxybenzylamine (1.31 g, 6.62 mmol), pyridine (1.05 g, 13.2mmol) and NMP (9.0 ml) was heated at 140° C. for 37 hours. The mixturewas cooled to ambient temperature and concentrated in vacuo. The residuewas purified by ISOLUTE® SCX-2 SPE column eluting with a mixture of MeOHand 2.0 M ammonia solution in MeOH (1:0 to 0:1 by volume). Furtherpurification by column chromatography on silica gel, eluting with amixture of 2.0 M ammonia solution in MeOH and DCM (0:1 to 1:19 byvolume), afforded the desired product as a pale yellow oil (0.83 g,100%).

LCMS (Method C): R_(t)=2.94 min, m/z [M+H]⁺=627/629.

f) Preparation of Intermediate 26

A stirred mixture of intermediate 25 (0.83 g, 1.23 mmol) and TFA (3.5ml, 45.8 mmol) under a nitrogen atmosphere was heated at 75° C. for 2hours. The mixture was cooled to ambient temperature and concentrated invacuo. The residue was purified by ISOLUTE® SCX-2 SPE column, elutingwith a mixture of MeOH and 2.0 M ammonia solution in MeOH (1:0 to 0:1 byvolume), to afford the desired product as a yellow foam (0.53 g, 90%).

LCMS (Method B): R_(t)=2.62 min, m/z [M+H]⁺=447/449.

Intermediate 27 was prepared by an analogous reaction protocol asintermediate 21 using the appropriate starting material (Table 4).

TABLE 4 Intermediate Structure Starting Materials LCMS Data 27

a) 5,7-Dichloro-2- trideuteromethyl- 2H-pyrazolo [4,3-d] pyrimidine b)Hexamethylditin R_(t) = 3.41 min, m/z [M + H]⁺ = 334/336 (Method A)

Intermediate 28 was prepared by an analogous reaction protocol asintermediate 22 using the appropriate starting materials (Table 5).

TABLE 5 Intermediate Structure Starting Materials LCMS Data 28

a) Intermediate 20 b) Intermediate 27 R_(t) = 4.99 min, m/z [M + H]⁺ =537/539/541 (Method C)

Intermediate 29 was prepared by an analogous reaction protocol asintermediate 23 using the appropriate starting material (Table 6).

TABLE 6 Intermediate Structure Starting Materials LCMS Data 29

Intermediate 28 R_(t) = 3.77 min, m/z [M + H]⁺ = 383/385/387 (Method B)

Intermediates 30 and 31 were prepared by an analogous reaction protocolas intermediate 25 using the appropriate starting materials (Table 7).

TABLE 7 Intermediate Structure Starting Materials LCMS Data 30

a) Intermediate 29 b) 3,4,5- Trimethoxybenzylamine R_(t) = 2.69 min, m/z[M + H]⁺ = 544/546 (Method C) 31

a) Intermediate 23 b) 3,4,5- Trimethoxybenzylamine R_(t) = 2.76 min, m/z[M + H]⁺ = 555/557 (Method C)

Intermediates 32 and 33 were prepared by an analogous reaction protocolas intermediate 26 using the appropriate starting material (Table 8).

TABLE 8 Intermediate Structure Starting Materials LCMS Data 32

Intermediate 30 R_(t) = 2.08/2.28 min, m/z [M + H]⁺ = 364/366 (Method B)33

Intermediate 31 R_(t) = 2.44 min, m/z [M + H]⁺ = 375/377 (Method C)

Example A6

a) Preparation of Intermediate 34

A stirred mixture of intermediate 13 (1.70 g, 3.46 mmol),3-iodo-azetidine-1-carboxylic acid tert-butyl ester (1.47 g, 5.18 mmol),Cs₂CO₃ (5.63 g, 17.3 mmol) and DMF (10 ml) was heated at 105° C. for 6.0hours. A second portion of 3-iodo-azetidine-1-carboxylic acid tert-butylester (0.32 g, 1.14 mmol) and Cs₂CO₃ (2.25g, 6.91 mmol) was added andthe resulting mixture was heated at 105° C. for 18 hours. The mixturewas cooled to ambient temperature and partitioned between water and DCM.The organic phase was dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel, elutingwith a mixture of MeOH and DCM (0:1 to 1:9 by volume), to afford thedesired product (1.79 g, 100%).

LCMS (Method C): R_(t)=4.25 min, m/z [M+H]⁺=532/534/536.

b) Preparation of Intermediate 35

A stirred solution of intermediate 34 (1.79 g, 3.36 mmol) in DCM (20 ml)under a nitrogen atmosphere at ambient temperature was treated with TFA(2.0 ml, 26.1 mmol), and the resulting mixture was stirred for 1 hour.The mixture was concentrated in vacuo to afford the desired product(1.84 g, 100%).

LCMS (Method C): R_(t)=2.27 min, m/z [M+H]^(|)=432/434/436.

c) Preparation of Intermediate 36

A stirred solution of intermediate 35 (1.84 g, 3.36 mmol) in a mixtureof MeOH (17 ml) and acetic acid (8.0 ml) under nitrogen atmosphere atambient temperature was treated with(1-ethoxycyclopropoxy)trimethylsilane (2.93 g, 16.8 mmol). Afterstirring for 10 minutes, the mixture was treated with sodiumcyanoborohydride (1.60 g, 25.4 mmol) and the resulting mixture wasstirred at 55° C. for 18 hours. The mixture was cooled to ambienttemperature and concentrated in vacuo. The residue was partitionedbetween DCM and 2.0 M aqueous sodium carbonate solution. The organicphase was dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by column chromatography on silica gel, eluting with a mixtureof MeOH and DCM (0:1 to 1:9 by volume), to afford the desired product asa pale yellow solid (0.55 g, 35%).

LCMS (Method B): R_(t)=2.41 min, m/z [M+H]⁺=472/474/476.

Intermediates 37 to 39 were prepared by an analogous reaction protocolas intermediate 34 using the appropriate starting materials (Table 9).

TABLE 9 Intermediate Structure Starting Materials LCMS Data 37

a) Intermediate 32 b) 3- Methanesulfonyloxy- pyrrolidine-1-carboxylicacid tert-butyl ester R_(t) = 2.77 min, m/z [M + H]⁺ = 533/535 (MethodC) 38

a) Intermediate 33 b) 3- Methanesulfonyloxy- pyrrolidine-1-carboxylicacid tert-butyl ester R_(t) = 2.87 min, m/z [M + H]⁺ = 544/546 (MethodC) 39

a) Intermediate 33 b) 3-Iodo-azetidine-1- carboxylic acid tert- butylester R_(t) = 2.93 min, m/z [M + H]⁺ = 530/532 (Method C)

Intermediates 40 to 42 were prepared by an analogous reaction protocolas intermediate 35 using the appropriate starting material (Table 10).

TABLE 10 Intermediate Structure Starting Materials LCMS Data 40

Intermediate 37 R_(t) = 0.31/1.85 min, m/z [M + H]⁺ = 433/435 (Method C)41

Intermediate 38 R_(t) = 0.27/1.96 min, m/z [M + H]⁺ = 444/446 (Method A)42

Intermediate 39 R_(t) = 0.33/1.88 min, m/z [M + H]⁺ = 430/432 (Method C)

Example A7

a) Preparation of Intermediate 43

A stirred solution of intermediate 35 (0.29 g, 0.67 mmol) in a mixtureof MeOH (20 ml) and 1,2-dichloroethane (10 ml) under a nitrogenatmosphere at ambient temperature was treated sequentially with sodiumacetate (0.06 g, 0.67 mmol), cyclopropanecarboxaldehyde (0.09 g, 0.67mmol) and sodium triacetoxyborohydride (0.28 g, 1.34 mmol), and theresulting mixture was stirred for 4 hours. The mixture was purified byISOLUTE® SCX-2 SPE column, eluting with a mixture of MeOH and 2.0 Mammonia solution in MeOH (1:0 to 0:1 by volume), to afford the desiredproduct as a pale yellow solid (0.26 g, 79%).

LCMS (Method B): R_(t)=2.36 min, m/z [M+H]⁺=486/488/490.

Intermediates 44 to 46 were prepared by an analogous reaction protocolas intermediate 43 using the appropriate starting materials (Table 11).

TABLE 11 Intermediate Structure Starting Materials LCMS Data 44

a) Intermediate 40 b) Acetaldehyde R_(t) = 0.32/1.82 min, m/z [M + H]⁺ =461/463 (Method C) 45

a) Intermediate 41 b) Acetaldehyde R_(t) = 0.32/2.06 min, m/z [M + H]⁺ =472/474 (Method C) 46

a) Intermediate 42 b) Cyclopropanecarboxaldehyde R_(t) = 1.80 min, m/z[M + H]⁺ = 484/486 (Method B)

Preparation of Compounds

The values of acid content (e.g. formic acid or acetic acid) in thecompounds as provided herein, are those obtained experimentally and mayvary when using different analytical methods. The content of formic acidor acetic acid reported herein was determined by ¹H NMR integration andis reported together with the ¹H NMR results.

Compounds with an acid content of below 0.5 equivalents may beconsidered as free bases.

Example B1

a) Preparation of Compound 1

A stirred mixture of intermediate 8 (0.04 g, 0.10 mmol),2-methyl-but-3-yn-2-ol (0.01 g, 0.13 mmol), tetrakis(triphenylphosphine)palladium (0.02 g, 0.02 mmol), copper(I) iodide (0.002 g, 0.011 mmol),Et₃N (0.10 ml, 0.74 mmol) and MeCN (1.0 ml) was heated by microwaveirradiation at 100° C. for 1 hour. The mixture was cooled to ambienttemperature and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel eluting with a mixture of 2.0 Mammonia solution in MeOH and DCM (0:1 to 1:9 by volume). Furtherpurification by trituration with Et₂O afforded the desired product as apale yellow solid (0.02 g, 50%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.95 (s, 1H), 8.93 (d, J=1.0 Hz, 1H),8.74 (d, J=1.0 Hz, 1H), 8.00 (s, 1H), 6.26 (s, 2H), 5.48 (s, 1H), 4.51(t, J=6.8 Hz, 2H), 4.16 (s, 3H), 3.29-3.26 (m, 2H), 3.24 (s, 3H),2.12-2.03 (m, 2H), 1.52 (s, 6H).

LCMS (Method E): R_(t)=2.32 min, m/z [M+H]⁺=420.

Compounds 2 to 4 were prepared by an analogous reaction protocol asExample B1 using the appropriate starting materials (Table 12).

TABLE 12 Compound Structure Starting Materials 2

a) Intermediate 8 b) 2-Cyclopropyl- but-3-yn-2-ol 3

a) Intermediate 26 b) 2-Cyclopropyl- but-3-yn-2-ol 4

a) Intermediate 26 b) 1,1,1-Trideutero-2- trideuteromethyl-3- butyn-2-ol

Example B2

a) Preparation of Compound 5

A degassed mixture of intermediate 44 (0.07 g, 0.15 mmol), intermediate1 (0.09 g, 0.30 mmol), tetrakis(triphenylphosphine) palladium (0.04 g,0.03 mmol), copper(I) iodide (0.003 g, 0.02 mmol), Et₃N (0.15 ml, 1.06mmol), MeCN (3.0 ml) and 1.0 M solution of TBAF in THF (0.08 ml, 0.08mmol) was heated by microwave irradiation at 100° C. for 1 hour. Themixture cooled to ambient temperature and concentrated in vacuo. Theresidue was partitioned between EtOAc and water, and the organic phasewas washed with brine, dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by ISOLUTE® SCX-2 SPE column washing with MeOH,followed by elution with 2.0 M ammonia in MeOH. Further purification byreverse phase preparative HPLC, eluting with a mixture of MeCN and watercontaining 0.1% formic acid (1:9 to 3:1 by volume over 20 minutes),afforded the desired product as a pale yellow solid (0.02 g, 32%,contains formic acid 1.0 equivalents).

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 9.20 (s, 1H), 8.84 (d, J=7.5 Hz, 1H),8.17 (s, 1H), 7.97 (s, 1H), 7.77 (d, J=10.7 Hz, 1H), 6.17 (s, 2H), 5.43(br. s, 1H), 5.22-5.15 (m, 1H), 3.19-3.09 (m, 2H), 2.68-2.52 (m, 4H),2.34-2.25 (m, 1H), 1.92-1.81 (m, 1H), 1.18 (t, J=7.2 Hz, 3H).

LCMS (Method E): R_(t)=2.11 min, m/z [M+H]⁺=471.

Compounds 6 and 7 were prepared by an analogous reaction protocol asExample B2 using the appropriate starting materials (Table 13).

TABLE 13 Compound Structure Starting Materials 6

a) Intermediate 45 b) Intermediate 1 7

a) Intermediate 46 b) Intermediate 1

Example B3

a) Preparation of Compound 8

A degassed mixture of intermediate 12 (0.21 g, 0.43 mmol), acetamide(0.03 g, 0.54 mmol), potassium carbonate (0.18 g, 1.28 mmol), palladium(II) acetate (0.01 g, 0.08 mmol), Xantphos (0.05 g, 0.09 mmol) and1,4-dioxane (4.0 ml) under an Argon atmosphere was heated by microwaveirradiation at 110° C. for 30 minutes. The mixture was cooled to ambienttemperature, filtered through Celite® and the filtrate concentrated invacuo. The residue was diluted with MeOH (8.0 ml), treated with 1.0 Maqueous sodium hydroxide solution (4.0 ml), and the resulting mixtureheated at reflux for 30 minutes. The mixture was cooled to ambienttemperature and partitioned between chloroform and water. The organicphase was dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by reverse phase preparative HPLC, eluting with a mixture ofMeCN and water containing 0.1% ammonium hydroxide (1:9 to 19:1 by volumeover 20 minutes), to afford the desired product as a pale yellow solid(0.08 g, 39%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.93 (d, J=1.0 Hz, 1H), 8.91 (s, 1H),8.72 (d, J=1.0 Hz, 1H), 8.11 (s, 1H), 6.24 (s, 2H), 5.33 (s, 1H), 4.51(t, J=6.7 Hz, 2H), 4.15-4.08 (m, 1H), 3.27 (t, J=6.0 Hz, 2H), 3.24 (s,3H), 2.12-2.02 (m, 2H), 1.54 (s, 3H), 1.38-1.32 (m, 2H), 1.20-1.11 (m,3H), 0.60-0.50 (m, 2H), 0.47-0.36 (m, 2H).

LCMS (Method E): R_(t)=2.84 min, m/z [M+H]⁺=472.

Compounds 9 to 12 were prepared by an analogous reaction protocol asExample B3 using the appropriate starting materials (Table 14).

TABLE 14 Compound Structure Starting Materials  9

a) Intermediate 15 b) Acetamide 10

a) Intermediate 16 b) Acetamide 11

a) Intermediate 17 b) Acetamide 12

a) Intermediate 18 b) Acetamide

Analytical Part

LCMS

Mass Spectrometry (LCMS) experiments to determine retention times andassociated mass ions were performed using the following methods:

Method A: Experiments were performed on a Waters ZMD quadrupole massspectrometer linked to a Waters 1525 LC system with a diode arraydetector. The spectrometer had an electrospray source operating inpositive and negative ion mode. Additional detection was achieved usinga Sedex 85 evaporative light scattering detector. LC was carried outusing a Luna 3 micron 30×4.6mm C18 column and a 2 mL/minute flow rate.The initial solvent system was 95% water containing 0.1% formic acid(solvent A) and 5% MeCN containing 0.1% formic acid (solvent B) for thefirst 0.5 minute followed by a gradient up to 5% solvent A and 95%solvent B over the next 4 min. The final solvent system was heldconstant for a further 1 minute.

Method B: Experiments were performed on a Waters VG Platform IIquadrupole spectrometer linked to a Hewlett Packard 1050 LC system witha diode array detector. The spectrometer had an electrospray sourceoperating in positive and negative ion mode. Additional detection wasachieved using a Sedex 85 evaporative light scattering detector. LC wascarried out using a Luna 3 micron 30×4.6mm C18 column and a 2 mL/minuteflow rate. The initial solvent system was 95% water containing 0.1%formic acid (solvent A) and 5% MeCN containing 0.1% formic acid (solventB) for the first 0.3 minute followed by a gradient up to 5% solvent Aand 95% solvent B over the next 4 min. The final solvent system was heldconstant for a further 1 minute.

Method C: Experiments were performed on a Waters Platform LC quadrupolemass spectrometer linked to a Hewlett Packard HP1100 LC system withdiode array detector. The spectrometer had an electrospray sourceoperating in positive and negative ion mode. Additional detection wasachieved using a Sedex 85 evaporative light scattering detector. LC wascarried out using a Phenomenex Luna 3micron 30×4.6mm C18 column and a 2mL/minute flow rate. The initial solvent system was 95% water containing0.1% formic acid (solvent A) and 5% MeCN containing 0.1% formic acid(solvent B) for the first 0.5 minute followed by a gradient up to 5%solvent A and 95% solvent B over the next 4 min. The final solventsystem was held constant for a further 1 minute.

Method D: Experiments were performed on a Waters ZQ quadrupole massspectrometer linked to a Hewlett Packard HP1100 LC system withquaternary pump and PDA detector. The spectrometer had an electrospraysource operating in positive and negative ion mode. Additional detectionwas achieved using a Sedex 65 evaporative light scattering detector. LCwas carried out using a Phenomenex Luna 3 micron 30×4.6mm C18 column anda 2 mL/minute flow rate. The initial solvent system was 95% watercontaining 0.1% formic acid (solvent A) and 5% MeCN containing 0.1%formic acid (solvent B) for the first 0.3 minute followed by a gradientup to 5% solvent A and 95% solvent B over the next 4 min. The finalsolvent system was held constant for a further 1 minute.

Method E: Experiments were performed on a Waters Micromass ZQ2000quadrupole mass spectrometer linked to a Waters Acquity UPLC system witha PDA UV detector. The spectrometer had an electrospray source operatingin positive and negative ion mode. LC was carried out using an AcquityBEH 1.7micron C18 column, an Acquity BEH Shield 1.7micron RP18 column oran Acquity HST 1.8micron column. Each column has dimensions of 100×2.1mmand was maintained at 40° C. with a flow rate of 0.4 mL/minute. Theinitial solvent system was 95% water containing 0.1% formic acid(solvent A) and 5% MeCN containing 0.1% formic acid (solvent B) for thefirst 0.4 minute followed by a gradient up to 5% solvent A and 95%solvent B over the next 5.2 min. The final solvent system was heldconstant for a further 0.8 min.

NMR Data

The NMR experiments herein were carried out using a Varian Unity Inovaspectrometer with standard pulse sequences, operating at 400 MHz atambient temperature. Chemical shifts (δ) are reported in parts permillion (ppm) downfield from tetramethylsilane (TMS), which was used asinternal standard. DMSO-d₆ (deuterated DMSO, dimethyl-d6 sulfoxide) wasused as solvent.

The values of acid content (e.g. formic acid or acetic acid) in thecompounds as provided herein, are those obtained experimentally and mayvary when using different analytical methods. The content of formic acidor acetic acid reported herein was determined by ¹H NMR integration.Compounds with an acid content of below 0.5 equivalents may beconsidered as free bases.

Compound 2

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.95 (s, 1H), 8.92 (d, J=0.9 Hz, 1H),8.72 (d, J=1.0 Hz, 1H), 8.00 (s, 1H), 6.23 (s, 2H), 5.33 (br. s, 1H),4.50 (t, J=6.8 Hz, 2H), 4.15 (s, 3H), 3.28 (t, J=6.1 Hz, 2H), 3.24 (s,3H), 2.11-2.02 (m, 2H), 1.54 (s, 3H), 1.21-1.13 (m, 1H), 0.62-0.48 (m,2H), 0.47-0.36 (m, 2H).

LCMS (Method E): R_(t)=2.52 min, m/z [M+H]⁺=446.

Compound 3 (Formic Acid 0.7 Equivalents)

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.85 (s, 1H), 8.83 (d, J=7.5 Hz, 1H),8.19 (s, 0.7H), 8.03 (s, 1H), 7.58 (d, J=10.4 Hz, 1H), 6.16 (s, 2H),5.33 (br. s, 1H), 4.42 (q, J=7.3 Hz, 2H), 4.35 (t, J=6.9 Hz, 2H),3.28-3.25 (m, 5H), 2.05-1.96 (m, 2H), 1.55 (s, 3H), 1.52 (t, J=7.3 Hz,3H), 1.19-1.12 (m, 1H), 0.64-0.58 (m, 1H), 0.53-0.46 (m, 1H), 0.46-0.36(m, 2H).

LCMS (Method E): R_(t)=3.73 min, m/z [M+H]⁺=477.

A second batch was isolated with 0.6 equivalents of formic acid present.

Compound 4 (Formic Acid 1.0 Equivalents)

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.85 (t, J=3.7 Hz, 2H), 8.13 (s, 1H),8.03 (s, 1H), 7.58 (d, J=10.4 Hz, 1H), 6.19 (s, 2H), 5.42 (br. s, 1H),4.42 (q, J=7.3 Hz, 2H), 4.35 (t, J=6.8 Hz, 2H), 3.28-3.25 (m, 5H),2.05-1.96 (m, 2H), 1.52 (t, J=7.3 Hz, 3H).

LCMS (Method E): R_(t)=3.45 min, m/z [M+H]⁺=457.

Compound 6

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 9.22 (s, 1H), 8.84 (d, J=7.6 Hz, 1H),8.02 (s, 1H), 7.76 (d, J=10.8 Hz, 1H), 6.17 (s, 2H), 5.42 (s, 1H),5.22-5.15 (m, 1H), 4.40 (q, J=7.3 Hz, 2H), 3.21-3.09 (m, 2H), 2.67-2.51(m, 4H), 2.32-2.24 (m, 1H), 1.91-1.81 (m, 1H), 1.54 (t, J=7.3 Hz, 3H),1.17 (t, J=7.2 Hz, 3H).

LCMS (Method E): R_(t)=2.22 min, m/z [M+H]⁺=482.

Compound 7

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 9.22 (s, 1H), 8.86 (d, J=7.5 Hz, 1H),8.05 (s, 1H), 7.69 (d, J=10.5 Hz, 1H), 6.22 (s, 2H), 5.44 (s, 1H),5.27-5.19 (m, 1H), 4.43 (q, J=7.3 Hz, 2H), 3.85 (t, J=7.6 Hz, 2H),3.45-3.40 (m, 2H), 2.43 (d, J=6.6 Hz, 2H), 1.56 (t, J=7.3 Hz, 3H),0.87-0.79 (m, 1H), 0.47-0.41 (m, 2H), 0.18-0.13 (m, 2H).

LCMS (Method E): R_(t)=2.30 min, m/z [M+H]⁺=494.

Compound 9

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.95 (s, 1H), 8.93 (d, J=1.0 Hz, 1H),8.73 (d, J=1.0 Hz, 1H), 8.06 (s, 1H), 6.23 (s, 2H), 5.33 (s, 1H), 4.51(t, J=6.5 Hz, 2H), 4.44 (q, J=7.3 Hz, 2H), 3.28-3.25 (m, 2H), 3.24 (s,3H), 2.11-2.03 (m, 2H), 1.56-1.51 (m, 6H), 1.21-1.13 (m, 1H), 0.62-0.49(m, 2H), 0.47-0.35 (m, 2H).

LCMS (Method E): R_(t)=2.77 min, m/z [M+H]⁺=460.

Compound 10

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 9.29 (s, 1H), 9.00 (d, J=1.0 Hz, 1H),8.74 (d, J=1.0 Hz, 1H), 8.07 (s, 1H), 6.26 (s, 2H), 5.39-5.32 (m, 2H),4.44 (q, J=7.3 Hz, 2H), 3.93 (t, J=7.6 Hz, 2H), 3.61-3.55 (m, 2H),2.12-2.05 (m, 1H), 1.59-1.54 (m, 6H), 1.22-1.14 (m, 1H), 0.63-0.49 (m,2H), 0.48-0.37 (m, 4H), 0.36-0.31 (m, 2H).

LCMS (Method E): R_(t)=2.17 min, m/z [M+H]⁺=483.

Compound 11

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 9.31 (s, 1H), 9.03 (d, J=1.0 Hz, 1H),8.76 (d, J=1.0 Hz, 1H), 8.07 (s, 1H), 6.28 (s, 2H), 5.47 (s, 1H),5.44-5.36 (m, 1H), 4.45 (q, J=7.3 Hz, 2H), 3.87 (t, J=7.6 Hz, 2H),3.52-3.47 (m, 2H), 2.44 (d, J=6.7 Hz, 2H), 1.56 (t, J=7.3 Hz, 3H),0.88-0.79 (m, 1H), 0.47-0.41 (m, 2H), 0.19-0.14 (m, 2H).

LCMS (Method E): R_(t)=1.96 min, m/z [M+H]⁺=477.

Compound 12 (Formic Acid 1.0 Equivalents)

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 9.30 (s, 1H), 9.00 (d, J=1.0 Hz, 1H),8.75 (d, J=1.1 Hz, 1H), 8.29 (s, 1H), 8.07 (s, 1H), 6.28 (s, 2H), 5.46(br. s, 1H), 5.40-5.33 (m, 1H), 4.44 (q, J=7.3 Hz, 2H), 3.93 (t, J=7.6Hz, 2H), 3.61-3.55 (m, 2H), 2.11-2.05 (m, 1H), 1.56 (t, J=7.3 Hz, 3H),0.47-0.41 (m, 2H), 0.37-0.33 (m, 2H).

LCMS (Method E): R_(t)=1.96 min, m/z [M+H]⁺=463.

Pharmacological Part

Biological Assay A

Inhibition of Auto-Phosphorylation of Recombinant HumanNF-kappaB-Inducing Kinase (NIK/MAP3K14) Activity (AlphaScreen®)

NIK/MAP3K14 auto-phosphorylation activity was measured using theAlphaScreen® (αscreen) format (Perkin Elmer). All compounds tested weredissolved in dimethyl sulfoxide (DMSO) and further dilutions were madein assay buffer. Final DMSO concentration was 1% (v/v) in assays. Assaybuffer was 50 mM Tris pH 7.5 containing 1 mM EGTA (ethylene glycoltetraacetic acid), 1 mM DTT (dithiothreitol), 0.1 mM Na₃VO₄, 5 mM MgCl₂,0.01% Tween® 20. Assays were carried out in 384 well Alphaplates (PerkinElmer). Incubations consisted of compound, 25 microMAdenosine-5′-triphosphate (ATP), and 0.2 nM NIK/MAP3K14. Incubationswere initiated by addition of GST-tagged NIK/MAP3K14 enzyme, carried outfor 1h at 25° C. and terminated by addition of stop buffer containinganti-phospho-IKK Ser176/180 antibody. Protein A Acceptor andGlutathione-Donor beads were added before reading using an EnVision®Multilabel Plate Reader (Perkin Elmer). Signal obtained in the wellscontaining blank samples was subtracted from all other wells and IC₅₀'swere determined by fitting a sigmoidal curve to % inhibition of controlversus Logio compound concentration.

Biological assay B

Effect of Compounds on P-IKKα Levels in L363 Cells

All compounds tested were dissolved in DMSO and further dilutions weremade in culture medium. Final DMSO concentration was 1% (v/v) in cellassays. The human L363 cells (ATCC) were cultured in RPMI 1640 mediumsupplemented with GlutaMax and 10% fetal calf serum (PAA). Cells wereroutinely maintained at densities of 0.2×10⁶ cells per ml—1×10⁶ cellsper ml at 37° C. in a humidified 5% CO₂ atmosphere. Cells were passagedtwice a week splitting back to obtain the low density. Cells were seededin 96 well plates (Nunc 167008) at 2×10⁶ per ml media in a volume of 75μl per well plus 25 μl 1 μg/ml recombinant human B-cell activatingfactor (BAFF/BLyS/TNFSF13B). Seeded cells were incubated at 37° C. in ahumidified 5% CO₂ atmosphere for 24 hr. Drugs and/or solvents were added(20 μl) to a final volume of 120 μl. Following 2 hr treatment plateswere removed from the incubator and cell lysis was achieved by theaddition of 30 μl 5× lysis buffer followed by shaking on a plate shakerat 4° C. for 10 min. At the end of this incubation lysed cells werecentrifuged at 800×g for 20 min at 4° C. and the lysate was assessed forP-IKKα levels by sandwich immuno-assay carried out in anti-rabbitantibody coated Mesoscale plates. Within an experiment, the results foreach treatment were the mean of 2 replicate wells. For initial screeningpurposes, compounds were tested using an 8 point dilution curve (serial1:3 dilutions). For each experiment, controls (containing MG132 and BAFFbut no test drug) and a blank incubation (containing MG132 and BAFF and10 μM ADS125117, a test concentration known to give full inhibition)were run in parallel. The blank incubation value was subtracted from allcontrol and sample values. To determine the IC₅₀ a sigmoidal curve wasfitted to the plot of % inhibition of control P-IKKα levels versus Log₁₀compound concentration.

Biological Assay C

Determination of Antiproliferative Activity on LP-1, L-363 and JJN-3Cells

All compounds tested were dissolved in DMSO and further dilutions weremade in culture medium. Final DMSO concentration was 0.3% (v/v) in cellproliferation assays. Viability was assessed using CellTiter-Glo cellviability assay kit (Promega). The human LP-1, L-363 and JJN-3 cells(DSMZ) were cultured in RPMI 1640 medium supplemented with 2 mML-glutamine, and 10% fetal calf serum (PAA). Cells were routinely keptas suspension cells at 37° C. in a humidified 5% CO₂ atmosphere. Cellswere passaged at a seeding density of 0.2×10⁶/ml twice a week. Cellswere seeded in black tissue culture treated 96-well plates (PerkinElmer). Densities used for plating ranged from 2,000 to 6,000 cells perwell in a total volume of 75 μl medium. After twenty four hours, drugsand/or solvents were added (25 μl) to a final volume of 100 μl.Following 72 hr of treatment plates were removed from the incubator andallowed to equilibrate to room temperature for approx 10 min. 100 μlCellTiter-Glo reagent was added to each well that was then covered(Perkin Elmer Topseal) and shaken on plate shaker for 10 min.Luminescence was measured on a HTS Topcount (Perkin Elmer). Within anexperiment, the results for each treatment were the mean of 2 replicatewells. For initial screening purposes, compounds were tested using a 9point dilution curve (serial 1:3 dilutions). For each experiment,controls (containing no drug) and a blank incubation (containing cellsread at the time of compound addition) were run in parallel. The blankvalue was subtracted from all control and sample values. For eachsample, the mean value for cell growth (in relative light units) wasexpressed as a percentage of the mean value for cell growth of thecontrol.

Data for the compounds of the invention in the above assays are providedin Table 15 (the values in Table 15 are averaged values over allmeasurements on all batches of a compound).

TABLE 15 Alpha- IKKα Screen Cellular JJN-3 L-363 LP-1 IC50 IC₅₀ EC₅₀EC₅₀ EC₅₀ Compound (nM) (nM) (nM) (nM) (nM) 1 46 n.c. 538 655 6783 2 23103 358 386 2957 3 992 n.c. 182 246 845 4 65 n.c. 102 69 244 5 112 n.c.46 52 128 6 37 n.c. 40 38 70 7 60 n.c. 95 53 202 8 38 n.c. 78 76 402 952 n.c. 217 162 629 10 186 n.c. 406 241 788 11 143 n.c. 158 62 1178 1284 n.c. 301 140 877 n.c.: not calculated

Prophetic Composition Examples

“Active ingredient” (a.i.) as used throughout these examples relates toa compound of Formula (I), including any tautomer or stereoisomeric formthereof, or a pharmaceutically acceptable addition salt, or a solvatethereof; in particular to any one of the exemplified compounds.

Typical examples of recipes for the formulation of the invention are asfollows:

1. Tablets

Active ingredient 5 to 50 mg Di-calcium phosphate 20 mg Lactose 30 mgTalcum 10 mg Magnesium stearate  5 mg Potato starch ad 200 mg

2. Suspension

An aqueous suspension is prepared for oral administration so that eachmilliliter contains 1 to 5 mg of active ingredient, 50 mg of sodiumcarboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol andwater ad 1 ml.

3. Injectable

A parenteral composition is prepared by stirring 1.5% (weight/volume) ofactive ingredient in 0.9% NaCl solution or in 10% by volume propyleneglycol in water.

4. Ointment

Active ingredient 5 to 1000 mg Stearyl alcohol 3 g Lanoline 5 g Whitepetroleum 15 g  Waler ad 100 g

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

1-14. (canceled)
 15. A method of treating or preventing a cellproliferative disease in a warm-blooded animal which comprisesadministering to the said animal an effective amount of a compound ofFormula (I):

or a tautomer or a stereoisomeric form thereof, wherein R¹ is selectedfrom the group of hydrogen; C₁₋₄alkyl; and C₁₋₄alkyl substituted withone or more fluoro substituents; R² is selected from the group ofhydrogen; C₁₋₄alkyl; C₁₋₄alkyl substituted with one or more fluorosubstituents; C₃₋₆cycloalkyl; and Het¹; or R¹ and R² together with thecarbon atom to which they are attached form a C₃₋₆cycloalkyl; Het¹ is aheteroaryl selected from the group of thienyl, thiazolyl, pyrrolyl,oxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl,pyridinyl and pyrimidinyl, each of which may be optionally substitutedwith one or two substituents independently selected from halogen, cyano,C₁₋₄alkyl, C₁₋₄alkyloxy, C₁₋₄alkyl substituted with one or more fluorosubstituents, and C₁₋₄alkyloxy substituted with one or more fluorosubstituents; X is N or CR⁹; R⁹ is selected from hydrogen and halogen;R³ is selected from the group of hydrogen; halogen; cyano;C₃₋₆cycloalkyl; C₁₋₆alkyl; Het⁴; C₁₋₆alkyl substituted with one or morefluoro substituents; —OC₁₋₆alkyl; —OC₁₋₆alkyl substituted with one ormore fluoro substituents; and C₁₋₆alkyl substituted with one substituentselected from —NR^(3a)R^(3b) and —OC₁₋₄alkyl; Het⁴ is a heteroarylselected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl,tetrahydrofuranyl, azetidinyl, piperazinyl, morpholinyl and oxetanyl,each of which may be optionally substituted with one or two substituentsindependently selected from fluoro, C₁₋₄alkyl, —OC₁₋₄alkyl,C₃₋₆cycloalkyl and C₁₋₄alkyl substituted with one or more fluorosubstituents; R^(3a) and R^(3b) are each independently selected fromhydrogen and C₁₋₄alkyl; R⁴ is hydrogen; R⁵ is selected from the group ofhydrogen; cyano; C₁₋₄alkyl; C₁₋₄alkyl substituted with one or morefluoro substituents; C₁₋₄alkyl substituted with one substituent selectedfrom the group of —NR^(5a)R^(5b), —OC₁₋₄alkyl, and Het⁵; R^(5a) andR^(5b) are each independently selected from the group of hydrogen andC₁₋₄alkyl; Het⁵ is a heterocyclyl selected from the group ofpiperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, pyrrolidinyl,tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may beoptionally substituted with one or two substituents independentlyselected from fluoro, C₁₋₄alkyl, —OC₁₋₄alkyl, C₃₋₆cycloalkyl andC₁₋₄alkyl substituted with one or more fluoro substituents; R⁶ isselected from the group of hydrogen; Het²; R⁸; C₁₋₆alkyl optionallysubstituted with one Het³; and C₂₋₆alkyl substituted with one or moresubstituents independently selected from the group of fluoro,—NR^(6a)R^(6b), and —OR^(6c); R^(6a), R^(6b) and R^(6c) are eachindependently selected from hydrogen and C₁₋₆alkyl; Het² is aheterocyclyl, bound through any available carbon atom, selected from thegroup of piperidinyl, tetrahydropyranyl, pyrrolidinyl,tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may beoptionally substituted with one or two substituents independentlyselected from fluoro, C₁₋₄alkyl, —OC₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkylsubstituted with one —OC₁₋₄alkyl, C₁₋₄alkyl substituted with oneC₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one or more fluorosubstituents; Het³ is a heterocyclyl selected from the group ofmorpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl,tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may beoptionally substituted with one or two substituents independentlyselected from fluoro, C₃₋₆cycloalkyl, C₁₋₄alkyl substituted with one—OC₁₋₄alkyl, C₁₋₄alkyl substituted with one C₃₋₆cycloalkyl, andC₁₋₄alkyl substituted with one or more fluoro substituents; R⁸ isC₃₋₆cycloalkyl optionally substituted with one or two substituentsindependently selected from fluoro, C₁₋₄alkyl, —OC₁₋₄alkyl, C₁₋₄alkylsubstituted with one —OC₁₋₄alkyl, and C₁₋₄alkyl substituted with one ormore fluoro substituents; R⁷ is selected from the group of hydrogen,C₁₋₆alkyl, C₃₋₆cycloalkyl and C₁₋₄alkyl substituted with one—OC₁₋₄alkyl; or a pharmaceutically acceptable addition salt, or asolvate thereof.
 16. The method according to claim 15, wherein R¹ isselected from the group of hydrogen; C₁₋₄alkyl; and C₁₋₄alkylsubstituted with one or more fluoro substituents; R² is selected fromthe group of C₁₋₄alkyl; C₁₋₄alkyl substituted with one or more fluorosubstituents; C₃₋₆cycloalkyl; and Het¹; or R¹ and R² together with thecarbon atom to which they are attached form a C₃₋₆cycloalkyl; Het¹ is aheteroaryl selected from the group of thienyl, thiazolyl, pyrrolyl,oxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl,pyridinyl and pyrimidinyl, each of which may be optionally substitutedwith one or two substituents independently selected from halogen, cyano,C₁₋₄alkyl, C₁₋₄alkyloxy, C₁₋₄alkyl substituted with one or more fluorosubstituents, and C₁₋₄alkyloxy substituted with one or more fluorosubstituents; X is N or CR⁹; R⁹ is selected from hydrogen and halogen;R³ is selected from the group of hydrogen; halogen; cyano;C₃₋₆cycloalkyl; C₁₋₆alkyl; C₁₋₆alkyl substituted with one or more fluorosubstituents; —OC₁₋₆alkyl; —OC₁₋₆alkyl substituted with one or morefluoro substituents; and C₁₋₆alkyl substituted with one substituentselected from —NR^(3a)R^(3b) and —OC₁₋₄alkyl; R^(3a) and R^(3b) are eachindependently selected from hydrogen and C₁₋₄alkyl; R⁴ is hydrogen; R⁵is selected from the group of hydrogen; cyano; C₁₋₄alkyl; C₁₋₄alkylsubstituted with one or more fluoro substituents; C₁₋₄alkyl substitutedwith one substituent selected from the group of —NR^(5a)R^(5b), and—OC₁₋₄alkyl; R^(5a) and R^(5b) are each independently selected from thegroup of hydrogen and C₁₋₄alkyl; R⁶ is selected from the group ofhydrogen; Het²; R⁸; C₁₋₆alkyl optionally substituted with one Het³; andC₂₋₆alkyl substituted with one or more substituents independentlyselected from the group of fluoro, —NR^(6a)R^(6b), and —OR^(6c); _(R)^(6a), R^(6b) and R^(6c) are each independently selected from hydrogenand C₁₋₆alkyl; Het² is a heterocyclyl, bound through any availablecarbon atom, selected from the group of piperidinyl, tetrahydropyranyl,pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of whichmay be optionally substituted with one or two substituents independentlyselected from fluoro, C₁₋₄alkyl, —OC₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkylsubstituted with one —OC₁₋₄alkyl, C₁₋₄alkyl substituted with oneC₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one or more fluorosubstituents; Het³ is a heterocyclyl selected from the group ofmorpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl,tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may beoptionally substituted with one or two substituents independentlyselected from fluoro, C₁₋₄alkyl, —OC₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkylsubstituted with one —OC₁₋₄alkyl, C₁₋₄alkyl substituted with oneC₃₋₆cycloalkyl, and C₁₋₄alkyl substituted with one or more fluorosubstituents; R⁸ is C₃₋₆cycloalkyl optionally substituted with one ortwo substituents independently selected from fluoro, C₁₋₄alkyl,—OC₁₋₄alkyl, C₁₋₄alkyl substituted with one —OC₁₋₄alkyl, and C₁₋₄alkylsubstituted with one or more fluoro substituents; R⁷ is selected fromthe group of hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl and C₁₋₄alkylsubstituted with one —OC₁₋₄alkyl.
 17. The method according to claim 15,wherein R¹ is C₁₋₄alkyl; R² is selected from the group of C₁₋₄alkyl; andC₃₋₆cycloalkyl; X is N or CR⁹; R⁹ is halogen; in particular fluoro; R³is hydrogen; R⁴ is hydrogen; R⁵ is hydrogen; R⁶ is selected from thegroup of Het²; and C₂₋₆alkyl substituted with one —OR^(6c); R^(6c) isC₁₋₆alkyl; Het² is a heterocyclyl, bound through any available carbonatom, selected from the group of pyrrolidinyl, and oxetanyl, each ofwhich may be optionally substituted with one or two substituentsindependently selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, and C₁₋₄alkylsubstituted with one C₃₋₆cycloalkyl; R⁷ is selected from the group ofC₁₋₆alkyl, and C₃₋₆cycloalkyl.
 18. The method according to claim 15,wherein R³ is hydrogen; and R⁵ is hydrogen.
 19. The method according toclaim 15, R⁶ is selected from the group of Het²; and C₂₋₆alkylsubstituted with one —OR^(6c).
 20. The compound according to claim 19,wherein R⁶ is selected from the group of


21. The method according to claims 15 to 20, R¹ is selected from thegroup of C₁₋₄alkyl; R² is selected from the group of C₁₋₄alkyl;C₁₋₄alkyl substituted with one or more fluoro substituentsC₃₋₆cycloalkyl; and Het¹; or R¹ and R² together with the carbon atom towhich they are attached form a C₃₋₆cycloalkyl.
 22. The method accordingto claims 15 to 20, wherein X is N.
 23. The method according to claims15 to 20, wherein X is CR⁹.
 24. The method according to claim 15,wherein the compound is selected from

tautomers and stereoisomeric forms thereof, and the pharmaceuticallyacceptable addition salts, and the solvates thereof.
 25. The methodaccording to claims 15 to 20, wherein the compound is in apharmaceutical composition comprising said compound and apharmaceutically acceptable carrier or diluent.
 26. The method accordingto claim 24, wherein the compound is in a pharmaceutical compositioncomprising said compound and a pharmaceutically acceptable carrier ordiluent.